Thursday, May 31, 2007

About 90 percent of CLL is sporadic, a germline mutation in gene for a micro RNA was discovered in 2005

RESEARCHERS DISCOVER AN INHERITED MUTATION FOR CHRONIC LYMPHOCYTIC LEUKEMIA Submitted by harminka to HULIQ on Thu, 2007-05-31 17:46.


Researchers have discovered the first inherited gene mutation that increases a person's risk for chronic lymphocytic leukemia (CLL), one of the most common forms of the disease.

The study shows that the inherited mutation greatly reduces the gene's protective activity. Furthermore, a second kind of change occurs later that turns the gene off altogether, leading to leukemia. This latter alteration is a chemical change that is not inherited.

The findings could help identify people at risk for chronic leukemia, but they also may provide new insights into the process of natural cell death. They may even lead to new strategies for treating the disease.

The research is to be published in the June 1 issue of the journal Cell. It was led by researchers at the Ohio State University Comprehensive Cancer Center
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About 90 percent of CLL cases are sporadic; that is, they have no genetic component.

But about one in 10 people with CLL have relatives who also develop the disease – strong evidence of a hereditary predisposition. However, usually only two or three people within a family are affected, making it difficult to do the genetic studies needed to find possible mutations, Plass says.

The family examined in this research was identified by collaborator Henry Lynch at Creighton University.

The researchers are now studying the chemical pathway that regulates the gene, considering possible therapies, working to identify other CLL families and looking for other predisposing genes.

In 2005, other Ohio State Comprehensive Cancer Center researchers discovered a germline mutation in a gene for a microRNA that is implicated in CLL, suggesting that this may also be a predisposing mutation for the disease. -Ohio State University



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1: N Engl J Med. 2005 Oct 27;353(17):1793-801. Links
Erratum in:
N Engl J Med. 2006 Aug 3;355(5):533.
Comment in:
N Engl J Med. 2005 Oct 27;353(17):1768-71.
N Engl J Med. 2006 Feb 2;354(5):524-5; author reply 524-5.
N Engl J Med. 2006 Feb 2;354(5):524-5; author reply 524-5.
A MicroRNA signature associated with prognosis and progression in chronic
lymphocytic leukemia.Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, Iuliano R, Palumbo T, Pichiorri F, Roldo C, Garzon R, Sevignani C, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM.
Department of Molecular Virology, Immunology, and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.

BACKGROUND: MicroRNA expression profiles can be used to distinguish normal B cells from malignant B cells in patients with chronic lymphocytic leukemia (CLL). We investigated whether microRNA profiles are associated with known prognostic factors in CLL. METHODS: We evaluated the microRNA expression profiles of 94 samples of CLL cells for which the level of expression of 70-kD zeta-associated protein (ZAP-70), the mutational status of the rearranged immunoglobulin heavy-chain variable-region (IgV(H) ) gene, and the time from diagnosis to initial treatment were known. We also investigated the genomic sequence of 42 microRNA genes to identify abnormalities. RESULTS: A unique microRNA expression signature composed of 13 genes (of 190 analyzed) differentiated cases of CLL with low levels of ZAP-70 expression from those with high levels and cases with unmutated IgV(H) from those with mutated IgV(H) . The same microRNA signature was also associated with the presence or absence of disease progression. We also identified a germ-line mutation in the miR-16-1-miR-15a primary precursor, which caused low levels of microRNA expression in vitro and in vivo and was associated with deletion of the normal allele. Germ-line or somatic mutations were found in 5 of 42 sequenced microRNAs in 11 of 75 patients with CLL, but no such mutations were found in 160 subjects without cancer (P<0.001). CONCLUSIONS: A unique microRNA signature is associated with prognostic factors and disease progression in CLL. Mutations in microRNA transcripts are common and may have functional importance. Copyright 2005 Massachusetts Medical Society.

PMID: 16251535 [PubMed - indexed for MEDLINE

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Wednesday, May 30, 2007

Nurses who work for drug companies


Nursing Drugmakers Back To Health
May 30th, 2007 8:23 am By Ed Silverman

Britain’s state-financed health-care system prides itself on providing care for all. But the system’s funding pinch is causing some doctors’ offices to rely on financial support from the pharmaceutical industry, The Wall Street Journal reports.

Drugmakers are paying for nurses to study patient charts to identify people with chronic illnesses. The nurses, who come from nursing contractors, then recommend which patients should be called in for a check-up and perhaps prescribed new treatment - sometimes a medicine made by the company funding the nurses. The work is part of what the industry calls “disease management programs,” which drugmakers say improve care for people with illnesses like diabetes, asthma or heart disease.

The risk, however, is that companies use the programs as a back door for marketing pills. The programs also raise concerns about patient privacy. Last fall, the Association of the British Pharmaceutical Industry, a trade group, temporarily suspended Merck’s UK subsidiary from its ranks after finding Merck used a program for patients with high blood pressure to promote its drug Cozaar.

Drug companies are “doing this on the hope that they will get their fair share of prescriptions out of it,” says Steve Kerridge, head of In2Focus, a U.K. firm that provides nurses for the projects.

Jim Kennedy, a physician from Middlesex, England, says he’s turned down offers from drug reps to send special nurse teams to his practice. There is a “perceived or real risk of the pharmaceutical companies’ interests taking precedence over the patients’ interests,” says Dr. Kennedy, who is also the spokesman for the Royal College of General Practitioners, a professional group. He says many doctors in his group share his concern.


This is the rest of the story that appears in The Wall Street Journal:

While company-sponsored nurse teams are most common in Britain, the practice is growing in other countries that also pay for medical care including Belgium, Germany and Ireland, says Hywell Evans, head of the European unit of Quintiles Transnational Corp., a company based in Research Triangle Park, N.C., that provides nurses and other services to drug companies.

The U.S. runs industry-sponsored disease-management programs, too, but most often are targeted at patients on Medicaid or Medicare. The biggest programs to date have been financed by Pfizer Inc., which has a subsidiary called Pfizer Health Solutions to manage the projects.

From 2001 through 2005, Pfizer sponsored a program for tens of thousands of Florida Medicaid patients with chronic illnesses such as asthma, diabetes and heart disease. A team of Pfizer-sponsored nurses and care managers kept in touch with patients by phone or through personal visits, encouraging them to eat well, exercise and take their medication. Pfizer promised to save the state money by reducing the patients’ need for costly emergency care. In return, Florida agreed to give Pfizer drugs preferred status in the Medicaid program. Opinions are divided as to whether the program saved Florida money.

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INCREASING PATERNAL AND NOT MATERNAL AGE FOUND IN NON-FAMILIAL AUTISM, HIGHEST RISK OF AUTISM WITH A FAMILY HISTORY OF AUTISM OR APSERGER'S AND OTHER

PDD IN SIBLINGS


1: J Child Psychol Psychiatry. 2005 Sep;46(9):963-71. Links
Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study.Lauritsen MB, Pedersen CB, Mortensen PB.
Centre for Basic Psychiatric Research, Psychiatric Hospital in Aarhus, Aarhus University Hospital, Denmark. mbl@psykiatri.aaa.dk

BACKGROUND: The etiology of autism is unknown. A strong genetic component has been detected but non-genetic factors may also be involved in the etiology. METHODS: We used data from the Danish Psychiatric Central Register and the Danish Civil Registration System to study some risk factors of autism, including place of birth, parental place of birth, parental age, family history of psychiatric disorders, and paternal identity. RESULTS: A total of 943,664 children younger than ten years were followed from 1994 to 2001; of those, 818 children developed autism. The highest risks of autism were found in siblings of children with autism, or Asperger's syndrome and other pervasive developmental disorders (PDDs), with relative risks of 22 and 13, respectively. The relative risk of autism in the child was about twice as high if the mother had been diagnosed with a psychiatric disorder. The risk of autism was associated with increasing degree of urbanisation of the child's place of birth and with increasing paternal, but not maternal, age. An increased relative risk of 1.4 was found if the mother was born outside Europe, and in children of parents who were born in different countries. CONCLUSIONS: The highest risk of autism was found in families with a history of autism, or Asperger's syndrome and other PDDs in siblings, supporting the commonly accepted knowledge that genetic factors are involved in the etiology of autism.

PMID: 16108999 [PubMed - indexed for MEDLINE]

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Tuesday, May 29, 2007

New Sporadic Breast Cancer Genes Identified




As more genes are identified, tests will become more predictive.

Douglas Easton, University of Cambridge




They identified 30 differences in single DNA bases that seemed to be linked to the disease. These were then compared in more than 20,000 women with breast cancer and in a similar number of controls. The results are reported in Nature1.





Reviews Genetics 1, 40-47 (2000); doi:10.1038/35049558




Summary

Germline base substitution mutations occur more frequently in males than in females, especially in older males.
The main explanation for the sex and age effect is that a much larger number of germline divisions occurs in the male than in the female, and continues throughout male adulthood.
Point mutations at some loci occur almost exclusively in males, whereas others have a smaller excess, roughly ten times more than in females. Which is more typical remains to be determined.
For mutations other than point mutations, sex biases in the mutation rate are very variable. However, small deletions are more frequent in females.
The total rate of new deleterious mutations for all genes is estimated to be about three per zygote. This value is uncertain, but it is likely that the number is greater than one.
It is suggested that quasi-truncation selection is the principal explanation for how the population can rid itself of a large number of mutations with a relatively low fitness cost.
Since this form of selection is effective only with sexual reproduction, perhaps the fact that humans reproduce sexually has made it possible to have such a long life cycle.


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Monday, May 28, 2007

IS THERE A CONNECTION BETWEEN OLDER PATERNAL AGE AND SPORADIC EARLY ONSET PARKINSON'S WILL ANYONE CHECK THIS OUT?

Is there a paternal age effect in Parkinson Disease is this a question that anyone is studying? Has it ever been studied? Would there be any funding to find out? Could there be de novo germ line mutations in the sporadic cases?



Genetic predisposition - Why do some patients with Parkinson’s disease develop symptoms at age 30 and others at age 60? Why do some patients do well on medications for many years while others have dose fluctuations early in the disease? Could a genetic predisposition be the determining factor? A major step towards the answer was the recent discovery of a specific gene in an Italian family with many members affected by the disease. A specific protein called a-synuclein was found to be abnormal in these patients. This exciting discovery will certainly contribute towards our understanding of Parkinson’s disease. There are nine genetic abnormalities that have been found to cause Parkinson's disease as of early 2002. However, most often a definite family history is NOT present for most patients. In these sporadic cases, a genetic predisposition may still play a role by increasing the change of getting the disease when patients are exposed to environmental insults.





Neurology. 2006 Feb 14;66(3):415-7. Links
Glucocerebrosidase gene mutations and Parkinson disease in the Norwegian population.Toft M, Pielsticker L, Ross OA, Aasly JO, Farrer MJ.
Department of Neuroscience, Norwegian University of Science and Technology, N-7489 Trondheim, Norway. mathias.toft@ntnu.no

An association between mutations in the glucocerebrosidase (GBA) gene and Parkinson disease (PD) was recently reported in Ashkenazi Jews. The authors screened a series of 311 Norwegian patients with PD and 474 controls for 2 common functional mutations of the GBA protein, N370S and L444P. Seven patients (2.3%) and 8 controls (1.7%) carried a mutant GBA allele (p = 0.58). This study does not indicate increased susceptibility to PD in GBA mutations carriers in Norway.




Genetic Testing in Parkinson's Disease
Genetic testing has recently become available for the parkin and PINK1 genes. Parkin is a large gene and testing is difficult. At the current stage of understanding, testing is likely to give a meaningful result only for people who develop the condition before the age of 30 years. Pink1 appears to be a rare cause of inherited Parkinson’s disease. A small percentage (~2 percent) of those developing the condition at an early age appear to carry mutations in the PINK1 gene.


Mol Genet Metab. 2007 Jun;91(2):195-200. Epub 2007 Apr 25. Links
Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease.Ziegler SG, Eblan MJ, Gutti U, Hruska KS, Stubblefield BK, Goker-Alpan O, Lamarca ME, Sidransky E.
Section on Molecular Neurogenetics, Medical Genetics Branch, NHGRI, NIH, Building 35, Room 1A213, Bethesda, MD, USA.


BACKGROUND: An association between glucocerebrosidase, the enzyme deficient in Gaucher disease, and the synucleinopathies has been suggested both by the development of parkinsonism in Gaucher probands and carriers, as well as by the presence of mutations in the gene for glucocerebrosidase (GBA) in different series of subjects with synucleinopathies. In this study, an open access Parkinson repository was used to establish the incidence of GBA alterations in a different ethnic cohort with sporadic Parkinson disease (PD). METHODS: The glucocerebrosidase gene was sequenced in samples collected from 92 Chinese Parkinson disease patients from Taiwan along with 92 clinically screened controls, matched for age and ethnicity. FINDINGS: The frequency of GBA mutations among the Chinese PD probands was 4.3%, in contrast to 1.1% in Chinese controls. Mutant alleles identified included two known mutations, L444P and D409H, and two novel mutations, L174P and Q497R. INTERPRETATION: These results, ascertained in subjects from Taiwan collected in a standardized and clinically rigorous open access Parkinson disease repository and screened by direct sequencing of GBA, demonstrate that GBA mutations are also encountered in Chinese subjects with sporadic PD at a higher frequency than many other known PD genes. The study demonstrates that the association of GBA mutations with the development of parkinsonian pathology is not related to ethnic origin.

1: Arch Neurol. 2007 Mar;64(3):425-30. Links
LRRK2 exon 41 mutations in sporadic Parkinson disease in Europeans.Lesage S, Janin S, Lohmann E, Leutenegger AL, Leclere L, Viallet F, Pollak P, Durif F, Thobois S, Layet V, Vidailhet M, Agid Y, Durr A, Brice A; French Parkinson's Disease Genetics Study Group; Bonnet AM, Borg M, Broussolle E, Damier P, Destee A, Martinez M, Penet C, Rasco O, Tison F, Tranchan C, Verin M.
Institut National de la Sante et de la Recherche Medicale Unite 679, Neurology and Experimental Therapeutics, and Faculte de Medecine, Universite Pierre et Marie Curie, 75651 Paris CEDEX 13, France.

BACKGROUND: Mutations in leucine-rich repeat kinase 2 gene (LRRK2), particularly the G2019S mutation in exon 41, have been detected in familial and sporadic Parkinson disease (PD) cases. OBJECTIVES: To assess the frequency of LRRK2 exon 41 mutations in a series of sporadic PD cases from Europe and to determine the clinical features of LRRK2 mutation carriers. DESIGN: We analyzed European cases of sporadic PD for the presence of LRRK2 exon 41 mutations. These mutations were screened by denaturing high-performance liquid chromatography, and abnormal chromatograph traces were investigated by direct sequencing to determine the exact nature of the variants. Early-onset sporadic PD cases were also screened for parkin mutations. The haplotypes associated with the G2019S mutation were determined. The clinical characteristics of patients carrying LRRK2 mutations were detailed. SETTING: French Network for the Study of Parkinson Disease Genetics. Patients Three hundred twenty patients with apparently sporadic PD from Europe. MAIN OUTCOME MEASURES: Results of genetic analyses. RESULTS: We found the G2019S mutation in 6 patients and identified 2 new variants (Y2006H and T2031S) in 1 patient each. Their clinical features were similar to those of typical PD. All G2019S mutation carriers shared a common haplotype. CONCLUSIONS: The G2019S mutation is almost as frequent in sporadic cases (1.9%) as in previously reported familial cases (2.9%) in Europe and occurs in the same common founder. We identified 2 novel variants. Although the phenotype of LRRK2 mutation carriers closely resembles that of typical PD, the age at onset was younger (29 years in 1 patient) than previously described, and 3 patients were improved by deep brain stimulation.




1: Neurology. 2007 May 8;68(19):1557-62. Links
ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease.Di Fonzo A, Chien HF, Socal M, Giraudo S, Tassorelli C, Iliceto G, Fabbrini G, Marconi R, Fincati E, Abbruzzese G, Marini P, Squitieri F, Horstink MW, Montagna P, Libera AD, Stocchi F, Goldwurm S, Ferreira JJ, Meco G, Martignoni E, Lopiano L, Jardim LB, Oostra BA, Barbosa ER; The Italian Parkinson Genetics Network; Bonifati V.
Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands. v.bonifati@erasmusmc.nl

OBJECTIVE: To assess the prevalence, nature, and associated phenotypes of ATP13A2 gene mutations among patients with juvenile parkinsonism (onset <21 years) or young onset (between 21 and 40 years) Parkinson disease (YOPD). METHODS: We studied 46 patients, mostly from Italy or Brazil, including 11 with juvenile parkinsonism and 35 with YOPD. Thirty-three cases were sporadic and 13 had positive family history compatible with autosomal recessive inheritance. Forty-two had only parkinsonian signs, while four (all juvenile-onset) had multisystemic involvement. The whole ATP13A2 coding region (29 exons) and exon-intron boundaries were sequenced from genomic DNA. RESULTS: A novel homozygous missense mutation (Gly504Arg) was identified in one sporadic case from Brazil with juvenile parkinsonism. This patient had symptoms onset at age 12, levodopa-responsive severe akinetic-rigid parkinsonism, levodopa-induced motor fluctuations and dyskinesias, severe visual hallucinations, and supranuclear vertical gaze paresis, but no pyramidal deficit nor dementia. Brain CT scan showed moderate diffuse atrophy. Furthermore, two Italian cases with YOPD without atypical features carried a novel missense mutation (Thr12Met, Gly533Arg) in single heterozygous state. CONCLUSIONS: We confirm that ATP13A2 homozygous mutations are associated with human parkinsonism, and expand the associated genotypic and clinical spectrum, by describing a homozygous missense mutation in this gene in a patient with a phenotype milder than that initially associated with ATP13A2 mutations (Kufor-Rakeb syndrome). Our data also suggest that ATP13A2 single heterozygous mutations might be etiologically relevant for patients with YOPD and further studies of this gene in Parkinson disease are warranted.

PMID: 17485642 [PubMed - in process

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Thursday, May 24, 2007

A. Alfred Taubman's $5 Million Gift for ALS most Lou Gehrig's Disease is sporadic with no family history, is paternal age involved?


$5M Gift Will Attack Lou Gehrig’s Disease from All Angles

ALS AMYOTROPHIC LATERAL SCLEROSIS LOU GEHRIG'S TAUBMAN GIFT


Twenty years ago, retail pioneer A. Alfred Taubman lost a good friend to Lou Gehrig’s disease. Now, the memory of that friend’s horrifying death has motivated him to support ALS research at the University of Michigan with a new $5 million gift and his share of the royalties from his new book.





Image Gallery

University of Michigan Health System
A. Alfred Taubman visits the laboratory of Eva Feldman, M.D., Ph.D., at the University of Michigan Medical School. His new $5 million gift to Dr. Feldman's team will support research on Lou Gehrig's disease, adding to $2 million he has already given to her lab.

Click image to view fullsize
Image 1 of 1






Newswise — Twenty years ago, retail pioneer and philanthropist A. Alfred Taubman lost a good friend to amyotrophic lateral sclerosis — a horrifying fatal disease that’s better known as Lou Gehrig’s disease or ALS.

The memory of watching New York Sen. Jacob Javits slowly succumb to the nerve-killing condition has never left Mr. Taubman’s mind. And that memory has motivated him to support ALS research at the University of Michigan Medical School and beyond.

Now, he has greatly increased that support, with a new $5 million gift, and the promise of even further funding when he also donates his share of the royalties from his new book, “Threshold Resistance.”

The gifts will go to support ALS studies led by U-M neurologist and scientist Eva Feldman, M.D., Ph.D., whose lab has already received two $1 million gifts from Mr. Taubman. She is considered a national leader in ALS treatment and research, and heads the U-M Program for Neurology Research and Discovery.

Together with a team at University of California, San Diego School of Medicine, led by Martin Marsala, M.D., associate professor of anesthesiology, Dr. Feldman and her team will work on several scientific fronts to try to stop or slow the disease. Working at first in animals, then in ALS patients, they hope to make quick progress.

Among the weapons they will deploy against ALS are genetic tools to keep nerve cells from dying, new ways of delivering promising drugs and genes directly into nerve cells, and a potential treatment based on injecting stem cells into the spinal cord. The latter approach, which will require the use of human embryonic stem cells, will be tested at UC San Diego where Dr. Marsala has received additional funding from the California Stem Cell Initiative for his work on spinal cord injury.

"It's hard to imagine a more devastating disease than ALS," says Mr. Taubman, "and we have some of the highest incidence rates in the country right here in Michigan. Dr. Feldman and her team are doing miraculous work, and it's important that they have the resources to build on their momentum. I'm not a doctor or a scientist, but I am an optimist who believes in the extraordinary possibilities of modern medicine. This is important work that must continue."

Dr. Feldman calls the gift a major boost to research. “Mr. Taubman’s generous funding allows us to venture into exciting new territory with stem cells. It gives our patients great hope that our new research with our California colleagues will translate the promise of stem cell technology into the reality of therapy for ALS patients.”

Dr. Marsala, who hosted Dr. Feldman recently for several weeks of collaborative research, is an expert on grafting new cells into the spinal cord, and has studied the use of stem cells to treat spinal injuries caused by interruptions in blood flow.

The use of this technique in ALS, which involves the death of the motor neurons that send signals to the muscles and control movement, could be a new frontier in treating the disease.

Already, Marsala and Feldman have performed preliminary research in animals. The promising results from this study, which have not yet been published, form the basis for one prong of the attack on ALS that will be supported by Mr. Taubman’s generous gifts.

If additional laboratory work proves successful, a clinical trial in ALS patients could begin within five years.

The other prongs of the attack involve two other laboratory-based approaches that could also lead to clinical trials. The first will develop a method to help ALS-affected nerve cells generate more of the molecules called growth factors that might keep them healthy.

Dr. Feldman and her team have already succeeded in creating a genetic snippet that can encourage cells to increase the number of times their genetic machinery reads the genetic blueprint for those growth factors. Preliminary results show that injecting that snippet, called a zinc finger transcription factor, into cells causes more of the growth factor VEGF to be produced – and enhances nerve regeneration. Further research on this approach will be made possible by the gift.

The research team also hopes to develop another genetic tool, called a silencing RNA sequence, to keep the cells of ALS patients from making mutant proteins involved in the disease.

For more information on the U-M Program for Neurology Research & Discovery, visit http://www.med.umich.edu/pnrd. Dr. Feldman is the DeJong Professor of Neurology at UMMS and directs the department’s ALS clinic, which is certified by the ALS Association.

The gifts from Mr. Taubman are part of the University-wide $2.5 billion Michigan Difference campaign.

Background information on Amyotrophic Lateral Sclerosis or Lou Gehrig’s disease:

Called a neurodegenerative disease because it causes nerve cells to weaken and die, ALS attacks a specific kind of nerve cell called a motor neuron – the type of cell that connects muscles to the spinal cord and brain, and transmits signals that enable us to move.

As motor neurons in the upper and lower parts of the body begin to be attacked, patients may experience painless weakness in their hands, feet, arms or legs. They may also begin to have trouble walking, speaking or swallowing. Over time, the degeneration continues – robbing each patient of the ability to move, speak and function on his or her own, and ultimately killing each patient within months or years.

ALS has its roots in genetic mutations, but many have not yet been discovered. A small minority of ALS cases are inherited by members of families affected by gene mutations. But the vast majority of the approximately 30,000 Americans who currently have the disease have a spontaneous form that can strike anyone, anywhere. Treatments have improved in recent years, but ALS still challenges doctors and scientists as one of the most baffling and tragic diseases. Only through research such as that being performed at U-M and UCSD will new options arise.

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Wednesday, May 23, 2007

A LETTER FROM MICHAEL MOORE:"SICKO" IS SOCKO IN CANNES


Posted on Pharma Gossip by the Insider

SiCKO - Mike writes
A Letter from Michael Moore: 'Sicko' is Socko in Cannes!

May 23rd, 2007

Friends,

Well, as you may have read by now, our premiere of "Sicko" at the Cannes Film Festival has been an overwhelming success. The 2,000 people inside the Lumiere Theater were alternately in tears and laughing during the two-hour film -- and when it was over, they gave it a standing ovation that seemed to go on for nearly 15 minutes! Many came up to me and said (and critics seem to agree) that this is my best film yet. I don't know about that, and it seems weird to compare any of these movies in the first place. But I do feel safe in saying that I am very, very happy with this film and I can't wait to show it to you when it opens on June 29th.

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WHICH GENOME VARIANTS REFLECT THE DISORDERS AND DISEASE THAT INCREASE WITH PATERNAL AGE?




Identifying genetic variants that influence gene activity in different populations: a region where the same group of SNPs are associated with altered levels of gene activity in four populations, each shown by differently coloured points that lie off the line. [Credit: Matt Hurles]

SContact: Don Powell
don@sanger.ac.uk
44-012-234-94956
Wellcome Trust Sanger Institute

Which genome variants matter?
Global survey of the consequences of small and large DNA variants in our genome
Findings published today in Science will accelerate the search for genes involved in human disease. The report provides a first genome-wide view of how the unique composition of genetic variation within each of us leads to unique patterns of gene activity.

By defining those genetic variants with a biological effect, the results will help prioritise regions of the genome that are investigated for association with disease. This is an important step to understanding links between genes and disease for individuals, and across populations.

The Human Genome Project gave us the instruction manual for building a human. The HapMap and Copy Number Variation (CNV) Projects developed indices of where to find differences in the manuals of different people. One of the challenges for research into variation and disease is that most variants have no consequence for our wellbeing.

The new study gives a global view of the consequences of those differences for gene activity. The work shows that activity of more than 1000 genes is affected by sequence variation and is the first map of human populations that identifies the most important fraction of DNA variation, that which directly affects gene activity.

The research was led by scientists from the Wellcome Trust Sanger Institute, together with colleagues from the University of Cambridge, Hospital for Sick Children/University of Toronto and Harvard Medical School/Brigham and Women's Hospital.

Using the HapMap series of cell samples from four populations, they measured the activity of more than 14,000 genes in cells grown in culture. The cell samples provide a snapshot of genetic activity in one cell type. The activity of each gene was then correlated with genetic variation nearby, as defined by the HapMap, an index of single-base changes (single nucleotide polymorphisms, or SNPs) and the new index of copy number variants (CNVs).

"We've been able to look back into our history and find changes that are older and likely to be shared among populations," explained Dr Manolis Dermitzakis, senior author and Project Leader at the Wellcome Trust Sanger Institute. "But we also find many that are newer and less widespread.

"These are part of our recent evolution and a step along the way to understanding the origin and personal consequences of genetic change, not least for our wellbeing. This is a first generation map of biologically important DNA sequence variation"...........

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Sunday, May 20, 2007

PATERNAL AGE AND PREECLAMPSIA


Paternal age and preeclampsia
Auteur(s) / Author(s)
HARLAP Susan (1) ; PALTIEL Ora (2) ; DEUTSCH Lisa (2) ; KNAANIE Ariella (2) ; MASALHA Sausan (2) ; TIRAM Efrat (2) ; CAPLAN Lee S. (3) ; MALASPINA Dolores (4) ; FRIEDLANDER Yechiel (2) ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) Department of Obstetrics and Gynecology and Kaplan Cancer Center, New York University School of Medicine, New York, NY, ETATS-UNIS
(2) Department of Social Medicine, Hebrew University-Hadassah School of Public Health, Jerusalem, ISRAEL
(3) Morehouse School of Medicine Prevention Research Center, Atlanta, GA, ETATS-UNIS
(4) Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and New York State Psychiatric Institute, New York, NY, ETATS-UNIS

Résumé / Abstract
Background. Paternal aging is associated with premeiotic damage to spermatogonia, a mechanism by which new point mutations are introduced into the gene pool. We hypothesized that paternal age might contribute to preeclampsia. Methods. We studied the incidence of preeclampsia in 81,213 deliveries surveyed in 1964-1976 in the Jerusalem Perinatal Study. We controlled for maternal age, parity and other risk factors using logistic regression. Results. Preeclampsia was reported in 1303 deliveries (1.6%). Compared with fathers age 25-34 years, the odds ratios (ORs) for preeclampsia were 1.24 (95% confidence interval = 1.05-1.46) for age 35-44 and 1.80 (1.40-2.31) for age 45+. For fathers age <25, the OR was 1.25 (1.04-1.51). Although weaker than maternal age effects, paternal effects were consistent within subgroups of other variables. Conclusions. These findings support the hypothesis that a modest proportion of preeclampsia might be explained by new mutations acquired from fathers and add to a growing body of evidence for paternal age effects in birth defects, neuropsychiatric disease and neoplasia.
Revue / Journal Title
Epidemiology (Epidemiology) ISSN 1044-3983
Source / Source
2002, vol. 13, no6, pp. 660-667 [8 page(s) (article)] (66 ref.)
Langue / Language
Anglais

Editeur / Publisher
Lippincott Williams & Wilkins, Philadelphia, PA, ETATS-UNIS (1990) (Revue)

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Saturday, May 19, 2007

ARE ALL KINDS OF AUTISMS AND SCHIZOPHRENIAS ON THE RISE BECAUSE MEN ARE FATHERING BABIES IN THEIR MID 30s AND BEYOND, WAY BEYOND?



Minding Your Mind



New Key to Autism


September 25, 2006


By Michael Craig Miller, M.D.
Harvard Medical School





Convincing Evidence

What Causes These Genetic Errors?
Should Older Men Stop Fathering Babies?
A study published in the September, 2006 issue of the Archives of General Psychiatry may give older prospective fathers pause before plunging into biological parenthood. The authors found a significant increase in the risk of autism and similar disorders as fathers got older


This is not the first discovery of its type. Healthcare professionals have long known that as parents age, the risk of giving birth to a child with certain illnesses goes up. Older mothers, for example, are more likely to have a child with Down syndrome. In recent years, studies have revealed a link between aging fathers and schizophrenia.

Until recently, health care professionals have focused almost exclusively on the mother's age as a risk factor for health problems in the child. But we now know that the father's age also adds to the risk of potentially devastating diseases. And there is no practical way to detect these illnesses during pregnancy. For those weighing the risks, the decision can be wrenching. Adoption and in some instances a sperm donation may be acceptable alternatives to older fathers wanting to build a healthy family.

Michael Craig Miller, M.D. is Editor in Chief of the Harvard Mental Health Letter. He is also associate physician at Beth Israel Deaconess Medical Center and assistant professor at Harvard Medical School. He has been practicing psychiatry for more than 25 years and teaches in the Harvard Longwood Psychiatry Residency Program.



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Friday, May 18, 2007

33.7 mean age in maternal grandfathers at birth of mother of studied boys with DUCHENNES MUSCULAR DYSTROPHY 29.5 mean age in controls


WHERE WERE YOU JERRY LEWIS ON THIS ALL THOSE YEARS YOU COULD HAVE DONE SOME GOOD BY WARNING MEN TO FATHER BEFORE 33.


Am J Med Genet. 1980;7(1):27-34. Links
Frequency of new mutants among boys with Duchenne muscular dystrophy.Bucher K, Ionasescu V, Hanson J.
Haldane's rule states that one-third of the cases of an X-linked recessive lethal should represent new mutations. This rule is derived under the assumptions that there is equilibrium between mutation and selection, that mutation rates in ova and sperm are equal, and that heterozygous and homozygous normal women have the same fitness. To test this rule for Duchenne muscular dystrophy (DMD), we have examined the mothers of 55 boys with DMD (16 familial and 39 isolated cases) and classified them as carriers or noncarriers on the basis of measures of ribosomal protein synthesis (RPS). Of the 55 mothers, only nine (16.4%) are classified as noncarriers, a figure significantly different from the expected one-third. When the analysis is limited to the 39 mothers of isolated cases, 23.1% (9/39) are classified as noncarriers, still significantly different than expected under Haldane's rule. Violation of any of the assumptions under which Haldane's rule is derived could lead to deviations from the expected one-third new mutants. We find the most likely explantation to be a higher male than female mutation rate. This is supported also by the finding that maternal grandfathers in whom a mutation occurred had higher mean age at birth of the carrier daughter (33.7 +/- 1.6) than did the general population or intrapedigree controls (29.5 +/- 1.3).

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Thursday, May 17, 2007

SPERM DONORS CUT-OFF AGE IS 35TH BIRTHDAY AT THIS CRYOBANK, S. AFRICAN BANK CUT-OFF 30TH BIRTHDAY, ARE THEY AWARE ?






Donor Standards

Our donors are recruited from the Northwest US. Most of our donors are either starting, currently involved with, or have finished their higher education at the time of their participation in our donor program. All donors are between 18 and 35 years of age in order to minimize age related genetic abnormalities. All donors are frozen in very limited quantities in order to guarantee that the number of pregnancies created from any one donor are limited. We stop further sales to new clients at 10 reported successes. Although all donor histories are reviewed to provide you with donors that should give you a great chance of concieving a healthy and normal baby, there is of course no way to guarantee such an outcome. As all donor family histories will present with their own unique positive and negative attributes, we encourage all clients to review donor information thoroughly prior to purchase and use of specimens.

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MORE SCHIZOPHRENIA IN OFFSPRING AT 35 AND ABOVE IS FOUND IN ALL STUDIES


1: Eur Psychiatry. 2007 Jan;22(1):22-6. Epub 2006 Dec 4. Links
Paternal ages below or above 35 years old are associated with a different risk of schizophrenia in the offspring.Wohl M, Gorwood P.
INSERM U675, 16 rue Henri Huchard 75018 Paris, France.

BACKGROUND: A link between older age of fatherhood and an increased risk of schizophrenia was detected in 1958. Since then, 10 studies attempted to replicate this result with different methods, on samples with different origins, using different age classes. Defining a cut-off at which the risk is significantly increased in the offspring could have an important impact on public health. METHODS: A meta-analysis (Meta Win) was performed, assessing the mean effect size for each age class, taking into account the difference in age class references, and the study design. RESULTS: An increased risk is detected when paternal age is below 20 (compared to 20-24), over 35 (compared to below 35), 39 (compared to less than 30), and 54 years old (compared to less than 25). Interestingly, 35 years appears nevertheless to be the lowest cut-off where the OR is always above 1, whatever the age class reference, and the smallest value where offspring of fathers below or above this age have a significantly different risk of schizophrenia. CONCLUSION: No threshold can be precisely defined, but convergent elements indicate ages below or above 35 years. Using homogeneous age ranges in future studies could help to clarify a precise threshold.

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Tuesday, May 15, 2007

PARENTAL AGES AT BIRTH OF CHILDREN WITH PERVASIVE DEVELOPMENTAL DISORDERS ARE HIGHER THAN THOSE IN THE GENERAL POPULATION


1: Psychiatry Clin Neurosci. 2007 Apr;61(2):200-2. Links
Parental ages at birth of children with pervasive developmental disorders are higher than those of children in the general population.Koyama T, Miyake Y, Kurita H.
Department of Mental Health Administration, National Institute of Mental Health, National Center for Neurology and Psychiatry, Kodaira, Tokyo, Japan. tomok@ncnp.go.jp


To examine whether parental ages at birth of children with pervasive developmental disorders (PDD) are elevated, maternal/paternal ages at birth of 309 PDD children born in 1993-2003 (mean age, 8.4 years) were compared with those of children in the Japanese national statistics (general population). The mean maternal/paternal ages (years) at birth of PDD children of 31.7/34.6 were significantly higher even than the highest mean maternal/paternal ages at birth of children of 31.2/33.6 in the national statistics in 2003. This first Japanese study to report elevated parental ages at birth of PDD children underscores the need of further extensive studies.

PMID: 17362441 [PubMed - indexed for MEDLINE]

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LINEAR RELATIONSHIP BETWEEN AGE AND INCREASING STRUCTURAL ABERRATIONS AND DISOMY FOR CHROMOSOME 9 IN HUMAN SPERM

European Journal of Human Genetics

Linear increase of structural and numerical
chromosome 9 abnormalities in human sperm
regarding age

Merce` Bosch1, Osvaldo Rajmil2, Josep Egozcue3 and Cristina Templado*,1
1Departament de Biologia Cel.lular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Auto`noma de
Barcelona, Bellaterra 08193, Spain; 2Servei d’Andrologia, Fundacio´ Puigvert, Barcelona 08025, Spain; 3Departament
de Biologia Cel.lular, Fisiologia i Immunologia, Facultat de Cie`ncies, Universitat Auto`noma de Barcelona, Bellaterra
08193, Spain
A simultaneous four-colour fluorescence in situ hybridisation (FISH) assay was used in human sperm in
order to search for a paternal age effect on: (1) the incidence of structural aberrations and aneuploidy of
chromosome 9, and (2) the sex ratio in both normal spermatozoa and spermatozoa with a numerical or
structural abnormality of chromosome 9. The sperm samples were collected from 18 healthy donors, aged
24–74 years (mean 48.8 years old). Specific probes for the subtelomeric 9q region (9qter), centromeric
regions of chromosomes 6 and 9, and the satellite III region of the Y chromosome were used for FISH
analysis. A total of 190 117 sperms were evaluated with a minimum of 10 000 sperm scored from each
donor. A significant linear increase in the overall level of duplications and deletions for the centromeric
and subtelomeric regions of chromosome 9 (Pr0.002), chromosome 9 disomy (Po0.0001) as well as
diploidy (Po0.0001) was detected in relation to age. The percentage of increase for each 10-year period
was 29% for chromosome 9 disomy, 18.8% for diploidy, and ranged from 14.6 to 28% for structural
aberrations. Our results indicate a linear increase in structural aberrations and disomy for chromosome 9 in
sperm with respect to age.
European Journal of Human Genetics (2003) 11, 754–759. doi:10.1038/sj.ejhg.5201049
Keywords: paternal age; spermatozoa; structural aberrations; aneuploidy; diploidy; sex ratio; chromosome 9;







In conclusion, a linear relationship between donor age
and increasing frequencies of structural chromosome
aberrations and disomy for chromosome 9, and diploidy
in human spermatozoa have been herein demonstrated.
Thus far, disomy frequencies for 11 of the 24 chromosomes
of the human sperm karyotype have been evaluated
by FISH in relation to age, while structural aberrations
have only been analysed for chromosomes 110 and 9
(present study). It would be necessary to include other
Figure 1 Relationship between age and frequencies of
numerical and structural abnormalities for chromosome 9,
and diploidy.
Age and chromosome abnormalities in human sperm
M Bosch et al
758
European Journal of Human Genetics
chromosomes in these studies to define the real effect of
advanced paternal age on chromosomal abnormalities in
sperm.
Acknowledgements
We thank Dr Pere Puig Casado for performing the statistical analysis
and also Mr Chuck Simmons for the revision and correction of the
English of this manuscript. This work received financial support from
Ministerio de Ciencia y Tecnologı´a (Project BFI2002-01193) and
Generalitat de Catalunya (CIRIT, 2001 SGR-00201), Spain.
References
1 Hassold T, Hunt PA: To err (meiotically) is human: the genesis of
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2 Jacobs P: The chromosome complement of human gametes.
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3 Olson SD, Magenis RE: Preferential paternal origin of de novo
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4 Estop AM, Ma´rquez C, Munne S et al: An analysis of human sperm
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10 McInnes B, Rademaker AW, Martin RH: Donor age and the
frequency of disomy for chromosomes 1, 13, 21 and structural
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11 Bosch M, Rajmil O, Martı´nez-Pasarell O, Egozcue J, Templado C:
Linear increase of diploidy in human sperm with age: a fourcolour
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12 Robbins WA, Baulch JE, Moore II D, Weier HU, Blakey D,
Wyrobek AJ: Three-probe fluorescence in situ hybridisation to
assess chromosome X, Y, and aneuploidy in sperm of 14 men
from two healthy groups: evidence for a paternal age effect on
sperm aneuploidy. Reprod Fertil Dev 1995; 7: 799– 809.
13 Luetjens CM, Rolf C, Gassner P, Werny JE, Nieschlag E: Sperm
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14 Rousseaux S, Hazzouri M, Pelletier R, Monteil M, Usson Y, Sele B:
Disomy rates for chromosomes 14 and 21 studied by fluorescent
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years of age. Mol Hum Reprod 1998; 4: 695– 699.
15 Griffin DK, Abruzzo MA, Millie EA et al: Nondisjunction in
human sperm: evidence for an age effect of increasing paternal
age. Hum Mol Genet 1995; 4: 2227– 2232.
16 Asada H, Sueoka K, Hashiba T, Kuroshima M, Kobayashi N,
Yoshimura Y: The effect of age and abnormal sperm count on the
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17 Kinakin B, Rademaker A, Martin R: Paternal age effect of YY
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18 Gardner RJM, Sutherland GR: Chromosome abnormalities
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chromosome 9 bands p12 and q13– 21.1 are involved in different
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Japanese: incidence, sex difference and clinical significance. Jpn J
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21 in human sperm by using primed in situ labeling technique.
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27 Rives N, Mazurier S, Bellet D, Joly G, Mace B: Assessment
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Cytogenet Cell Genet 1990; 53: 103– 107.
29 Guttenbach M, Engel W, Schmid M: Analysis of structural and
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31 Renaud H, Gasser SM: Heterochromatin: a meiotic matchmaker?
Trends Cell Biol 1997; 7: 201–205.
32 Amiel A, Sardos-Albertini F, Fejgin MD, Sharony R, Diukman R,
Bartoov B: Interchromosomal effect leading to an increase in
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245– 250.
33 Serra A, Brahe C, Millington-Ward A et al: Pericentric inversion of
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34 Mroz K, Hassold TJ, Hunt PA: Meiotic aneuploidy in the XXY
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35 Egozcue S, Blanco J, Vendrell JM et al: Human male infertility:
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THESE HEART DEFECTS INCREASE WITH PATERNAL AGE VSD VENTRICULAR SEPTAL DEFECTS, ATRIAL SEPTAL DEFECTS AND PATENT DUCTUS ARTERIOSUS

Teratology

Volume 50, Issue 1 , Pages 80 - 84
Published Online: 8 Jun 2005


Paternal age and the risk of congenital heart defects
Andrew F. Olshan, Ph.D. 1 2 *, Patricia G. Schnitzer 1, Patricia A. Baird 3
1Department of Epidemiology, School of Public Health, University of North, Carolina, Chapel Hill, North Carolina 27599
2University of North Carolina Birth Defects Center, Chapel Hill, North Carolina 27599
3Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada


*Correspondence to Andrew F. Olshan, Department of Epidemiology, CB# 7400 McGarvran-Greenberg Hall, Unversity of North Carolina, Chapel Hill, NC 27599

Abstract
The effect of paternal age on the risk of birth defects among affspring is less well studied than the effect of maternal age, with few comprehensive epidemiologic studies having been conducted. Advanced paternal age has been shown to be associated with an increase in new dominant mutations that result in particular congenital anomalies. The relationship between paternal age more common birth defects, for example, cardiac defects, has not been as extensively evaluated. Therefore, a total of 4, 110 cases of congenital heart defects was identified from the British Columbia Health Surveillance Registry. Matched controls were obtained from the birth files of British Columbia for the years 1952-1973. Prevalence odds ratios for paternal age, adjusted for maternal age and other factors, were estimated for 8 cardiac defect groups.
A suggestive general pattern of increasing risk with increasing age among cases (excluding chromosomal anomalies) relative to controls was found for ventricular septal defects (VSD), atrial septal defects (ASD), and patent ductus arteriosus (PDA). In addition, an increased risk among men younger than 20 yr was found for VSD and ASD. These findings are consistent with the results of some previous epidemiologic studies. Based on the results of the study it is estimated that for cardiac defects such as VSD, approximately 5% of cases may be due to advanced paternal age (>35yr), Possibly through dominant mutations. © 1994 Wiley-Liss, Inc.



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Received: 22 March 1994; Accepted: 23 March 1994
Digital Object Identifier (DOI)

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Sunday, May 13, 2007

MANY EXAMPLES OF DISEASES RESULTING FROM CHANGES IN COPY NUMBERS PROBABLY SOMETHING TO DUE WITH EGGS & SPERM



Charles Lee, Ph.D.

This analysis of so-called copy number variation (CNV) has now revealed some startling results.

It would seem the assumption that the DNA of any two humans is 99.9% similar in content and identity no longer holds.

The researchers were astonished to locate 1,447 CNVs in nearly 2,900 genes, the starting "templates" written in the DNA that are used by cells to make the proteins which drive our bodies.

This is a huge, hitherto unrecognised, level of variation between one individual and the next.

"Each one of us has a unique pattern of gains and losses of complete sections of DNA," said Matthew Hurles, of the UK's Wellcome Trust Sanger Institute.

"One of the real surprises of these results was just how much of our DNA varies in copy number. We estimate this to be at least 12% of the genome.

"The copy number variation that researchers had seen before was simply the tip of the iceberg, while the bulk lay submerged, undetected. We now appreciate the immense contribution of this phenomenon to genetic differences between individuals."

Evolving story

The new understanding will change the way in which scientists search for genes involved in disease.


"Many examples of diseases resulting from changes in copy number are emerging," commented Charles Lee, one of the project's leaders from Brigham and Women's Hospital and Harvard Medical School in Boston, US.

"A recent review lists 17 conditions of the nervous system alone - including Parkinson's disease and Alzheimer's disease - that can result from such copy number changes."

Scientists are not sure why the copy variations emerge, but it probably has something to do with the shuffling of genetic material that occurs in the production of eggs and sperm; the process is prone to errors.

As well as aiding the investigation of disease and the development of new drugs, the research will also inform the study of human evolution, which probes genetic variation in modern populations for what it can say about their relationship to ancestral peoples.

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285 of the approximately 3,000 CNVs are already known to be
associated with disease, and copy number variations of some of
these genes have been or are now being speculated as risk
factors for ailments such as AIDS, inflammatory bowel disease, lupus, cataracts, arterial disease and
schizophrenia.

One interesting observation that the researchers made during this study was that many of the CNVs have
population-specific characteristics and frequencies, which could explain increased prevalence of some diseases in
certain populations. For example, previous research found that the deletion of the UGT2B17 gene may lead to an
increased risk of prostate cancer in African American men. As a result of this and other research, the consortium is
expanding their studies to thousands of healthy individuals from populations outside of the HapMap collection.

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HYPERCHOLESTEROLEMIA IN ASPERGER SYNDROME

DOES THIS HAVE ANYTHING TO DO WITH, IN SPORADIC CASES, HAVING AN OLDER FATHER AT THE TIME OF CONCEPTION OR A MATERNAL GRANDFATHER WHO WAS OLDER WHEN ONES MOTHER WAS BORN?


Brief report

Hypercholesterolemia in Asperger syndrome: Independence from lifestyle, obsessive–compulsive behavior, and social anxiety

Isabel Dziobeka, b, Stefan M. Golda, Oliver T. Wolfb and Antonio Convita, c, ,
aCenter for Brain Health, HN-400, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
bDepartment of Psychology, University of Bielefeld, Germany
cNathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA
Received 16 October 2005; revised 19 December 2005; accepted 5 February 2006.

We report on elevated total cholesterol and low-density lipoprotein (LDL) levels in 22 individuals with Asperger syndrome compared with well-matched controls, after accounting for lifestyle variables and clinical symptomatology that could affect them. A potential role for dyslipidemia in the pathogenesis of some forms of autism is discussed.

Keywords: Autism; Lipid profile; Etiology



Corresponding author. Tel.: +1 212 263 7565; fax: +1 212 263 3270.

Psychiatry Research
Volume 149, Issues 1-3, 15 January 2007, Pages 321-324

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TYPE 2 DIABETES, ALZHEIMER'S PATERNAL AGE, HYPERCHOLESTEROLEMIA

THIS MAY BE OFF TOPIC FOR A KNOWN PATERNAL AGE EFFECT BUT STUDIES CONCERNING PATERNAL AGE ARE NOT FORTHCOMING, SO WHY NOT SPECULATE A POSSIBLE CONNECTION?

Rev Diabet Stud. 2006 Winter;3(4):161-8. Epub 2007 Feb 10. Links
Diabetes and Alzheimer's disease - is there a connection?Sima AA, Li ZG.
Departments of Pathology, Wayne State University, School of Medicine, Detroit, MI 48201, USA.

It has been known for some time that diabetes may be associated with impaired cognitive function. During the last decade, epidemiological data have emerged suggesting a linkage between diabetes, particularly type 2 diabetes, and Alzheimer's disease (AD). There is evidence to suggest that impaired activities of neurotrophic factors such as insulin, IGF-1 and NGF, which occur in both diabetes and AD, may provide a mechanistic link between the two disorders. An additional probable factor that has been less evaluated to date is hypercholesterolemia, a common accompaniment to type 2 diabetes. Increased cholesterol availability is believed to play a crucial role in the abnormal metabolism of amyloid precursor protein leading to accumulation of amyloid-beta. Impaired insulin signaling in particular appears to be involved in hyperphosphorylation of the tau protein, which constitutes neurofibrillary tangles in AD. The linkage between abnormal amyloid metabolism and phosphor-tau is likely to be provided by the activation of caspases both by increased amyloid-beta and by impaired insulin signaling. Although the details of many of these components still await evaluation, it appears clear that commonalities exist in the underlying pathogenesis of diabetes and Alzheimer's disease. In this review we provide a brief update on linkages between these two diverse but common disorders.

PMID: 17487340 [PubMed

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Saturday, May 12, 2007

TATUM BABY DAUGHTER OF DEREK FISHER UTAH JAZZ PT GUARD Retinoblastoma is sometimes due to paternal age >= 45 YEAR WAS 3.0(95 % ci: 0.2-41.7)


Tatum, the little daughter of Utah Jazz point guard Derek Fisher has been diagnosed with a type of cancer called retinoblastoma

It is being reported that the little 10-month-old daughter of Utah Jazz point guard Derek Fisher is in hospital with a very serious medical condition.

Tatum Fisher has recently been diagnosed with a type of cancer known as retinoblastoma, which is a cancer of the eye. Treatment options include, removal of the eye, or a combination of chemotherapy and surgery.

The little girl's condition was first identified by her mother who noticed a weird reflection of light coming from her eye. A few doctor visits and a pediatrician visit later the family learned of the troubling diagnosis.

Doctors at New York Presbyterian Hospital performed a procedure on the baby girl in which they injected chemotherapy drugs directly into the tumor hoping to shrink it. If three such surgeries do not shrink the tumor to the point where it can be removed, then the little girl will lose her eye altogether.

“My wife and I definitely plan to try and help as many people as we can,” Fisher said. “I don’t know how we’ll be able to at this point. If there’s a treatment out there, they should be able to get it. Some people can’t afford to get it. Some people don’t have the resources.

"They've done nine cases," Fisher said. "(In) one case the child's arterial structure wasn't strong enough, but the other eight kids that had the treatment, all of their tumors have reduced in size."

Twin brother of Tatum, little Drew Fisher was also examined for signs of the condition however he is perfectly healthy.










1: Int J Epidemiol. 2001 Dec;30(6):1428-37. Links
Comment in:
Int J Epidemiol. 2001 Dec;30(6):1438-9.
Case-control study of parental age, parity and socioeconomic level in relation to childhood cancers.Dockerty JD, Draper G, Vincent T, Rowan SD, Bunch KJ.
Childhood Cancer Research Group, Department of Paediatrics, University of Oxford, 57 Woodstock Road, Oxford OX2 6HJ, UK.


BACKGROUND: Parental ages, parity, and social class have been found in some studies to be associated with particular childhood cancers. Further investigation is warranted because of conflicting findings, biases, and the need to test specific hypotheses. METHODS: A case-control study was conducted (England and Wales, ages 0-14 years). Cases were ascertained from the National Registry of Childhood Tumours, and were born and diagnosed during 1968-1986. Birth record controls were matched 1:1 to cases on date of birth, sex and area. Information on variables of interest for both groups came from birth records. In all, 10 162 pairs could contribute to matched analyses. RESULTS: The odds ratio (OR) for retinoblastoma resulting from assumed new germ cell mutations among children of fathers aged > or =45 years was 3.0 (95% CI : 0.2-41.7). The risk of childhood acute lymphoblastic leukaemia (ALL) was significantly higher among children of older mothers and fathers, and significant trends with increasing mothers' (P < 0.001) and fathers' (P = 0.002) ages were found. There was a strong and significant protective effect of increasing parity on risk of childhood ALL. The adjusted OR for parity of > or =5 (versus 0) was 0.5 (95% CI : 0.3-0.8). Children in more deprived communities had a lower risk of ALL; but this was not significant after confounders were allowed for. There was no significant effect of social class based on parental occupation on ALL risk, but the numbers were small in those analyses. CONCLUSIONS: The associations between ALL and parental ages did not disappear when children with Down syndrome were excluded, suggesting an additional explanation beyond known links. The strong ALL association with parity may be because of an unknown


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1: Ophthalmic Epidemiol. 2000 Dec;7(4):285-91. Links
Parental age in Indian patients with sporadic hereditary retinoblastoma.Sivakumaran TA, Ghose S, Kumar H, A S, Kucheria K.
Division of Genetics, Department of Anatomy, Dr. Rajendra Prasad Centre for Ophthalmic Science, All India Institute of Medical Sciences, New Delhi, India.

There is a consistent correlation between sporadic hereditary retinoblastoma and parental age. It has been proven beyond doubt that the birth rank is correlated with parental age. In the present study, a test for the effect of birth rank was performed in order to assess the risk of developing retinoblastoma with increased parental age. The study of the effect of birth rank showed a significant association between sporadic retinoblastoma (bilateral and unilateral) and late para, indicating that fresh germline mutations must have taken place in some of the sporadic cases. An investigation of the effect of birth rank on familial cases, obtained from published papers and our own series, showed that familial retinoblastoma is significantly associated with early para, suggesting early parental age. Further analysis of the mean paternal and maternal ages of sporadic cases (bilateral and unilateral) showed that the mean paternal age of sporadic bilateral (sporadic hereditary) cases was higher than that of sporadic unilateral cases (p<0.05). No such correlation was seen with mean maternal age. Thus, the present study shows that a high paternal age may be associated with sporadic bilateral (sporadic hereditary) retinoblastoma.

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1: Am J Ophthalmol. 1990 Dec 15;110(6):605-9. Links
Parental age in sporadic hereditary retinoblastoma.DerKinderen DJ, Koten JW, Tan KE, Beemer FA, Van Romunde LK, Den Otter W.
Department of Pathology, Academisch Ziekenhuis Utrecht, The Netherlands.
Of 104 children with sporadic hereditary retinoblastoma born between 1945 and 1970, we studied the age of their parents at the birth and compared this age with the mean age of parents at the birth of their children during the same period in The Netherlands. The mean age of fathers at the birth of their children with sporadic hereditary retinoblastoma (33.7 years) was significantly higher than the mean age of fathers at the birth of their children in the general population (32.5 years) (P less than .05, one sided). Similarly, the mean age of mothers at the birth of their children with sporadic hereditary retinoblastoma (31.2 years) was significantly higher than the mean age of mothers at the birth of their children in the general population (29.5 years) (P less than .05, one sided). We further analyzed this parental age factor by measuring the relative risk of age groups and comparing the incidence of sporadic hereditary retinoblastoma in the various parental age groups with the incidence of sporadic hereditary retinoblastoma in the total population. Mothers 35 years of age or older had a relative risk of 1.7 to have a child with sporadic hereditary retinoblastoma compared with mothers in the population in general (P = .006, one sided). Similarly, fathers 50 years of age or older had a relative risk of 5.0 to have a child with sporadic hereditary retinoblastoma compared with fathers in the population in general (P = .04, one sided). No parental age effect was found in children with nonhereditary retinoblastoma. We conclude that a high paternal and a high maternal age are significant risk factors for sporadic hereditary retinoblastoma.


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INCIDENCE OF WILM'S TUMOR INCREASED WITH PATERNAL AGING


Br J Cancer. 1993 Apr;67(4):813-8. Links
Wilms' tumour and parental age: a report from the National Wilms' Tumour Study.Olson JM, Breslow NE, Beckwith JB.
Department of Biostatistics, University of Washington, Seattle 98195.

Age distributions of parents at birth of patients registered in the National Wilms' Tumour Study were compared to those of the general population. An increasing incidence of sporadic Wilms' tumour with increasing paternal age was found, with a relative risk of 2.1 of tumour in children of fathers over 55 compared to children of fathers younger than 20. A similar effect for maternal age was found, with a relative risk of 1.4 in children of mothers over 40 compared to children of mothers younger than 20. The maternal age effect was much weaker among patients registered later in the study; in the later, more completely ascertained cohort, paternal age appears to be the major contributor to the parental age effect. Little difference in paternal age distribution was found between patients with bilateral and unilateral tumour and between male and female patients. In contrast, patients with reported associated congenital anomalies, patients with evidence of nephrogenic rests, and patients with early or late age-of-onset of tumour had parents who were, on average, substantially older than the remainder. These findings lend support to the idea that many Wilms' tumours result from new germline mutations. Further, the histologic composition of such tumours may be sufficiently distinct as to provide a valuable diagnostic indicator of the etiology of these tumours.

PMID: 8385980 [PubMed - indexed for MEDLINE]





Epidemiol. 1999 Apr;13(2):138-43. Links
Comment in:
Paediatr Perinat Epidemiol. 2000 Jul;14(3):283-5.
The influence of parental age on the risk of Wilms' tumour.Sharpe CR, Franco EL, de Camargo B, Lopes LF, Barreto J, Johnsson R, Mauad M.
Department of Epidemiology & Biostatistics, McGill University, Montreal, Canada.

The Brazilian Wilms' Tumour Study Group carried out a hospital-based multicentre case-control study of potential risk factors for the disease between April 1987 and January 1989. The parents of 109 cases of Wilms' tumour (WT) were interviewed when they were admitted to hospital for diagnosis and treatment. Also interviewed were the parents of two controls per case, matched for age, sex and interviewer, who were admitted to the same or nearby hospitals for treatment of non-neoplastic conditions. Odds ratios adjusted for family income and parental education were calculated by conditional logistic regression. Among cases diagnosed before 25 months of age there was a marked gradient of increasing risk of WT with increasing maternal age at the time of the child's birth. There was no increased risk for cases diagnosed after 25 months of age. The effects of paternal age were less marked. Possible explanations for these are discussed.

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THE OPTIMAL TIME FOR A MAN TO FATHER A HEALTHY CHILD IS...25 OR SO, SAYS DOLORES MALASPINA


Dolores Malaspina, MD


Like eggs, sperm have a "best by" date?


By Faye Flam

By the time I'd reached my early 30s and was still not married, someone offered me this bit of advice: Just pick somebody.

Women are relentlessly reminded of the dreaded biological clock and the risks of having children after 35. But recent science suggests men, too, should be worried.

"The term 'biological clock' has always referred to females, but now there's evidence men are also ticking off some of their healthy children," says Jay Schinfeld, a fertility specialist.

The latest finding, published last month: Older fathers are more likely to have children with autism. Researchers tracked 387,000 people born in Israel and concluded the odds of fathering an autistic child are about 6 in 1,000 for men under 20. When a man reaches 50, those odds shoot up to about 52 in 1,000.

"The optimal time for a man to father a healthy child is the same as for a woman — 25 or so," says Dolores Malaspina, a psychiatry professor at New York University and coauthor of the study.

Malaspina led an earlier study showing a connection between paternal age and schizophrenia. She found children born to fathers over 50 carried about three times the risk of developing schizophrenia as those born to fathers in their 20s.

Autism and schizophrenia both arise from a little-understood combination of genetic and environmental triggers. Both disorders tend to run in families, suggesting that genetic risk factors can be inherited.

But you don't have to carry a genetic disease to pass one on — the trouble can start in your testicles. There, sperm-generating cells divide about 23 times a year, in the process slowly accumulating copying errors.

Older fathers are more likely to have children with achondroplasia (dwarfism) and several other conditions caused by spelling errors in the DNA. So for a man, the older you get, the less your child's genetic endowment will resemble your own.

For women, aging isn't as likely to lead to spelling errors because we make no new eggs after we're born. But that leads to other problems. The million or so we begin life with die at a rate of about 30 a day, and as the remaining eggs age, they get less adept at one of their critical jobs — dividing their 46 chromosomes in half. Eggs don't do this until after they're penetrated by a sperm.

If they get it wrong, some will get extra chromosomes, others will miss one, leading to Down syndrome (an extra chromosome 21), Turner's syndrome (a missing X chromosome in a girl), and Klinefelter's syndrome (an extra X chromosome in a boy).

Menopause creates a natural cutoff for women's fertility around 50, while an increasing number of men much older than that are becoming fathers, or trying to, says Abington's Schinfeld. "We get some as old as 70 coming here to try to make babies," he says.

Some get married a second time to a younger woman and others find love late in life. Schinfeld said one of his patients, a Vietnam veteran in his 60s, came to him with a wife in her 30s. The man explained that during the war he'd rescued a group of villagers, including a little girl, and that girl tracked him down after she grew up. Despite the age difference, they fell in love and got married.

It's hard to say whether men will now be subject to pressure the way women are, or accused of "wanting it all."

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WHY AREN'T WE EXTINCT? ....................


Absolute Mutation Rate
JAMES F. CROW

"The total mutation frequency,as inferred from evolutionary studies,44), is something in the order of 100 new mutations per generation. This seems utterly frightening. Surely the overwhelming majority of these must be essentiallt neutral. More relevant is the frequency of new deleterious mutations, which is more than one per zygote.45)That is still high. WHY AREN'T WE EXTINCT?" emphasis mine




Department of Genetics, University of Wisconsin
: J Radiat Res (Tokyo). 2006;47 Suppl B:B75-82. Links
Age and sex effects on human mutation rates: an old problem with new complexities.Crow JF..


Base substitution mutations are far more common in human males than in females, and the frequency increases with paternal age. Both can be accounted for by the greater number of pre-meiotic cell divisions in males, especially old ones. In contrast, small deletions do not show any important age effect and occur with approximately equal frequency in the two sexes. Mutations in most genes include both types, and the sex and paternal age effect depends on the proportion of the two types. A few traits, of which Apert Syndrome is best understood, are mutation hot spots with all the mutations occurring in one or two codons, usually at one nucleotide. They occur with very high frequency almost exclusively in males and the frequency increases rapidly with paternal age. It has been suggested that the mutant cells have a selective advantage in the male germ-line prior to meiosis. Evidence for this surprising, but important, hypothesis is discussed. A possible mechanism is the conversion of asymmetrical stem-cell divisions into symmetric ones. Some traits with complex etiology show a slight paternal age effect. There is also a short discussion of the high deleterious mutation rate and the role of sexual reproduction in reducing the consequent mutation load.

PMID: 17019055 [PubMed - in process]


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October 2003, Volume 11, Number 10, Pages 754-759
Table of contents Previous Article Next PDF


LINEAR INCREASE OF STRUCTURAL AND NUMERICAL CHROMOSOME 9 ABNORMALITIES IN HUMAN SPERM REGARDING AGE

Mercè Bosch1, Osvaldo Rajmil2, Josep Egozcue3 and Cristina Templado1

1Departament de Biologia Cel.lular, Fisiologia i Immunologia,
Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain

2Servei d'Andrologia, Fundació Puigvert, Barcelona 08025, Spain

3Departament de Biologia Cel.lular, Fisiologia i Immunologia, Facultat de Ciències, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain

Correspondence to: C Templado, Departament de Biologia, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain. Tel: +34 93 -581 3569; Fax: +34 93 581 1025; E-mail: cristina.templado@uab.es


Abstract

A simultaneous four-colour fluorescence in situ hybridisation (FISH) assay was used in human sperm in order to search for a paternal age effect on: (1) the incidence of structural aberrations and aneuploidy of chromosome 9, and (2) the sex ratio in both normal spermatozoa and spermatozoa with a numerical or structural abnormality of chromosome 9. The sperm samples were collected from 18 healthy donors, aged 24-74 years (mean 48.8 years old). Specific probes for the subtelomeric 9q region (9qter), centromeric regions of chromosomes 6 and 9, and the satellite III region of the Y chromosome were used for FISH analysis. A total of 190 117 sperms were evaluated with a minimum of 10 000 sperm scored from each donor. A significant linear increase in the overall level of duplications and deletions for the centromeric and subtelomeric regions of chromosome 9 (P0.002), chromosome 9 disomy (P<0.0001) as well as diploidy (P<0.0001) was detected in relation to age. The percentage of increase for each 10-year period was 29% for chromosome 9 disomy, 18.8% for diploidy, and ranged from 14.6 to 28% for structural aberrations. Our results indicate a linear increase in structural aberrations and disomy for chromosome 9 in sperm with respect to age.

European Journal of Human Genetics

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ANOREXIA AND BULIMIA GENETIC 2007----1974 ANOREXIA PARENTS MUCH OLDER

Genetic Risk Factors For Eating Disorders Discovered
Science Daily — Until recently, it was generally believed that eating disorders such as anorexia nervosa and bulimia nervosa resulted solely from environmental influences such as peer pressure and certain perceived expectations of society.
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But research at Michigan State University has found that there are genetic risk factors at work as well. The research of Kelly Klump, an MSU associate professor of psychology, published in the May issue of Psychological Medicine, indicates that the origin of eating disorders has biological roots, similar to how bipolar disorder and schizophrenia are thought to have biological causes.

Specifically, Klump’s work found that when girls enter puberty their chances of developing such a disease grow rapidly.

“During puberty, there is an increased risk for developing an eating disorder,” said Klump. “Up to 50 percent of this risk can be attributed to genetic factors that emerge during puberty.”

Klump’s research looked at more than 500 female 14-year-old twins who were examined using sophisticated statistical modeling techniques. It was found that before puberty, environmental factors alone contribute to the development of various eating disorders. As puberty progresses, the genetic risk is activated and increases in importance to accounting for more than half the risk for eating pathology.

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Psychosomatic Medicine Vol. 36, No. 1 (Jan.-Feb. 1974)
Anorexia Nervosa:
Demographic and Clinical Features in 94 Cases

KATHERINE A. HALMI, MD
A comprehensive chart study was made of numerous clinical and demographic features in 94
patients with anorexia nervosa. Unlike other large series, this survey included the pediatric age
group. A significantly greater maternal and paternal age at time of the patient's birth and a
greater incidence of both low and high birth weights compared with the general population was
found. A relatively high occurrence of premorbid feeding problems was present. Anxiety and
obsessive-compulsive traits were frequent premorbid symptoms. Precipitating events were
identified more frequently in patients with a greater age at onset of illness. Characteristic
behavior noted during the course of this illness is described.




The mothers' age at time of the patients'
birth was significantly greater (p < .001,
Kolmogorov-Smirnov goodness fit test)
than that for national control mothers (14)
or Iowa control mothers2 (Fig. 1). Also,
the fathers' age at the time of the patients'
birth was significantly greater (p < .05,
Kolmogorov-Smirnov goodness-of-fit test)
than that of national control fathers (15)
(Fig. 2). A significantly higher mothers'
age at the time of probands' birth compared
to that of Swedish control mothers
was also reported by Theander (1). Kay
and Leigh (11) did not analyze their data
statistically, but nonetheless stated that
youthfulness or advanced age of mothers
at the patients' birth appeared unimportant.


SUMMARY
Significant demographic characteristics
found in this survey of the hospital
records of 94 anorexia patients include a
greater maternal and paternal age at time
of the probands' birth and a greater
incidence of both low and high birth
weights than in the general population.
Unlike other large series of anorexia
nervosa patients, this survey included the
pediatric age group. This would explain
the relatively high incidence, 8%, of onset
of illness prior to age 10.

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Friday, May 11, 2007

PSYCHOTIC DISORDERS, DECREASED LEARNING CAPACITY AND/OR MENTAL RETARDATION

TO REPEAT AN OLD POSTING ON OLDER PATERNAL AGE AND DETRIMENTAL OUTCOMES IN CHILDREN

Table II. Long-term effects of paternal ageing on offspring from table on page 2373 of Long –term effects of delayed parenthood by J.J. Tarin, J. Brines, and A. Cano

Dominant disorders
Wilms tumour, thanatophoric dysplasia, retinitis pigmentosa, osteogenisis imperfecta type IIA, acrodysostosis, achondroplasia, Apert’s disease, fibrodysplasia ossificans progressiva, aniridia, bilateral retinoblastoma, multiple exostoses, Marfan’s, Lesch-Nyan’s, Pfeiffer’s, Wardenburg’s, Treacher-Collins, Soto’s, and Crouzon’s syndromes, basel cell nevus, cleidocranial dysostosis, polyposis coli, oculodentodigital syndrome, Costello syndrome , progeria, Recklinghausen’s neurofibromatosis, tuberous sclerosis and renal polycystic kidney disease.

X-linked recessive diseases
Haemophilia A and Duchenne’s muscular dystrophy

Non-cytogenetic congential defects
Congential cataracts, reduction defects of the upper limb, nasal aplasia, pulmonic and urethtal stenosis, perauricular cyst, cleft palate,1 neural tube defects

Athetoid /dystonic cerebral palsy and congenital hemiplegia

Psychotic disorders

Decreased learning capacity and/or mental retardation

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Almost all cases of HGPS (PROGERIA) studied so far turn out to be new mutations of paternal origin with a paternal age effect by about FIVE YEARS

Origin of de novo mutation. As with de novo mutations in achondroplasia, all informative LMNA mutations have been paternal in origin, though the number of families evaluated is small [Eriksson et al 2003]. A paternal age effect is present as the father's age is significantly increased by about five years on average. There is no increase in consanguinity.



Am J Clin Nutr. 1992 Jun;55(6 Suppl):1222S-1224S. Links
Progeria: a human-disease model of accelerated aging.Brown WT.
Department of Human Genetics, New York State Institute for Basic Research, Staten Island 10314.

Progeria is a rare genetic disease with striking features that resemble accelerated aging. The inheritance pattern, paternal age effect, and lack of consanguinity argue that it is due to a sporadic dominant mutation. We have observed elevated levels of hyaluronic acid (HA) excretion in progeria patients. In several progeria patients we observed normal levels of growth hormone (GH) but very low levels of insulin-like growth factor I along with very high basal metabolic rates (BMRs). A trial of GH treatment was begun, which resulted in a marked increase in linear growth and a paradoxical drop in BMRs in these two patients. We hypothesize that the failure of patients with progeria to thrive may be due to a bioinactive form of GH and a lack of vasculogenesis caused by excess HA. An understanding of the progeria genetic mutation may define a key gene with a major effect on normal aging.






: Nature. 2003 May 15;423(6937):293-8. Epub 2003 Apr 25. Links
Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome.Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS. Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing. Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder. The HGPS gene was initially localized to chromosome 1q by observing two cases of uniparental isodisomy of 1q-the inheritance of both copies of this material from one parent-and one case with a 6-megabase paternal interstitial deletion. Sequencing of LMNA, located in this interval and previously implicated in several other heritable disorders, revealed that 18 out of 20 classical cases of HGPS harboured an identical de novo (that is, newly arisen and not inherited) single-base substitution, G608G(GGC > GGT), within exon 11. One additional case was identified with a different substitution within the same codon. Both of these mutations result in activation of a cryptic splice site within exon 11, resulting in production of a protein product that deletes 50 amino acids near the carboxy terminus. Immunofluorescence of HGPS fibroblasts with antibodies directed against lamin A revealed that many cells show visible abnormalities of the nuclear membrane. The discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing.

PMID: 12714972 [PubMed - indexed for MEDLINE]



1: Clin Genet. 2004 Jan;65(1):52-4. Links
Paternal origin of LMNA mutations in Hutchinson-Gilford progeria.D'Apice MR, Tenconi R, Mammi I, van den Ende J, Novelli G.
PMID: 15032975 [PubMed - indexed for MEDLINE]




FRANCIS COLLINS


"Almost all cases of HGPS studied so far turn out to be new mutations of paternal origin. Consistent with this, the age of fathers of children with HGPS is on the average slightly older than the general population of fathers. You can read more about this in the entry on progeria in GeneClinics.org"

paternal age effect is present as the father's age is significantly increased by about five years on average. There is no increase in consanguinity.




: Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):4949-54. Epub 2007 Mar 14. Links
A lamin A protein isoform overexpressed in Hutchinson-Gilford progeria syndrome interferes with mitosis in progeria and normal cells.Cao K, Capell BC, Erdos MR, Djabali K, Collins FS.
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by dramatic premature aging. Classic HGPS is caused by a de novo point mutation in exon 11 (residue 1824, C --> T) of the LMNA gene, activating a cryptic splice donor and resulting in a mutant lamin A (LA) protein termed "progerin/LADelta50" that lacks the normal cleavage site to remove a C-terminal farnesyl group. During interphase, irreversibly farnesylated progerin/LADelta50 anchors to the nuclear membrane and causes characteristic nuclear blebbing. Progerin/LADelta50's localization and behavior during mitosis, however, are completely unknown. Here, we report that progerin/LADelta50 mislocalizes into insoluble cytoplasmic aggregates and membranes during mitosis and causes abnormal chromosome segregation and binucleation. These phenotypes are largely rescued with either farnesyltransferase inhibitors or a farnesylation-incompetent mutant progerin/LADelta50. Furthermore, we demonstrate that small amounts of progerin/LADelta50 exist in normal fibroblasts, and a significant percentage of these progerin/LADelta50-expressing normal cells are binucleated, implicating progerin/LADelta50 as causing similar mitotic defects in the normal aging process. Our findings present evidence of mitotic abnormality in HGPS and may shed light on the general phenomenon of aging.

PMID: 17360355 [PubMed - indexed for MEDLINE]

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