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]
"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]