Thursday, January 15, 2009

Recurrent Microdeletions Cause Common Epilepsies

Recurrent Microdeletions Cause Common Epilepsies
Main Category: Epilepsy
Also Included In: Genetics
Article Date: 15 Jan 2009 - 1:00 PST

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In a research paper published in the journal Nature Genetics, an international consortium of researchers led by the European EPICURE consortium has identified losses of genomic sequence of 1.5 million base pairs (termed microdeletion) on the long arm of chromosome 15 (band 15q13.3) as a major risk factor for common epilepsies. Epilepsies belong to the most common diseases of the central nervous system and affect 3% of the population during life-time and up to 30 million people worldwide. About 50% of epilepsies have a strong genetic contribution. In large families with several affected family members, about twenty epilepsy genes have been identified, most of them encoding ion channel genes. However, these genes account only for a very small proportion of the genetic variance of epilepsy and the majority of genetic risk factors remain elusive. To dissect genetic risk factors, the research groups of the EPICURE consortium focus on a common form of genetically determined epilepsies, classified as idiopathic generalised epilepsy (IGE) that accounts for one third of all epilepsies. Accumulating evidence emphasizes that genomic structural variants, such as deletions, duplications, insertions and inversions of DNA segments (> 1 kb), affect approximately 5% of the human genome and have a substantial impact on human diversity and disease susceptibility. The US research group led by Evan Eichler (Department of Genomic Science, University of Washington, Seattle, USA) systematically investigates genomic structural variations using array-based technologies covering genetic markers in hot spot regions prone for structural rearrangements. Thereby, Andrew Sharp and colleagues identified a recurrent microdeletion on chromosome 15q13.3 that occurred in 0.3% of individuals with intellectual disability frequently combined with epilepsy. This microdeletion was absent in a large number of healthy controls. The obvious link to epilepsy motivated the authors to search for an involvement of the 15q13.3 deletion in the development of IGE.

Using high-density arrays covering the target region on 15q13.3, the German research teams of Ingo Helbig (Department of Neuropaediatrics, Christian-Albrechts-University, Kiel) and Thomas Sander (Cologne Center of Genomics, Cologne) discovered a significant association of the 15q13.3 microdeletion with IGE in patients collected by the EPICURE consortium. This association could be confirmed in a second independent IGE sample. Together, the 15q13.3 deletion was found in 1% (12 out of 1223) of IGE patients whereas none of 3669 control individuals carried this deletion. This finding suggests that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified so far.

Considering that the 15q13.3 deletions has been found also in 0.2 - 0.3% in patients affected by schizophrenia, autism and other psychiatric disorders, the involvement of this microdeletion in such a broad spectrum of diseases of the central nervous system implicates a non-specific impairment of neurodevelopment. In addition, other genetic and environmental factors appear to be responsible for the development of a certain neuropsychiatric disease. The concerted action of several risk factors might also explain the remarkable differences in the disease severity and the variability of the disease features observed in individuals carrying the 15q13.3 deletion. Taking into account the phenotypic spectrum attributable to the 15q13.3 deletion ranges from apparently unaffected individuals to severely affected patients suffering from mental retardation, dysmorphic features and epilepsy, it remains difficult to use this risk factor for genetic counseling, in particular in face of any therapeutically consequences.

The microdeletion on 15q13.3 contains at least seven genes. The gene encoding the ?7 subunit of the neuronal nicotinergic acetylcholine receptor (CHRNA7) is considered as a high-ranking candidate gene for the epilepsy phenotype. The CHRNA7 gene is expressed in the brain and rare mutations in two genes coding for three other subunits of nicotinergic acetylcholine receptors (CHRNA2, CHRNA4, and CHRNB2) have been identified in large families with several members affected by epilepsy. Further research on the 15q13.3 deletion and additional contributing genetic factors will be necessary to unravel the molecular mechanisms leading to epilepsy. One of the next steps should be molecular genetic analyses of the remaining apparently "normal" 15q13.3 region of the normally pairwise chromosomes.

Following up this key finding, we will achieve deeper insights into molecular mechanisms involved in a broad range of neuropsychiatric disorders and in particular epilepsy, which appears the disorder with the highest prevalence of the15q13.3 deletion observed so far. Of course, the final aim will be to transfer this knowledge into novel treatment strategies. At this point we are still at the beginning of the molecular genetic exploration of epilepsies. The 15q13.3 deletion seems to be an important piece of the puzzle and will lead our research interests to further studies elucidating the impact of structural variations of the human genome on the risk for epilepsy. At this stage of research, collaborative efforts of international research groups are essential to disentangle the complex genetics of epilepsy.

Universitaet zu Koeln / University of Cologne



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