Identification of COL6A2 mutations in progressive myoclonus epilepsy syndrome
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In this study, a consanguineous family with progressive myoclonus epilepsy (PME) was clinically examined and molecularly investigated to determine the molecular events causing disease. Since exclusion of known genes indicated that novel genes causing PME still remained unidentified, homozygosity mapping, exome sequencing, as well as validation and disease-segregation analyses were subsequently carried out for both loci and gene identification. To further assure our results, a muscle biopsy and gene expression analyses were additionally performed. As a result, a homozygous, disease-segregating COL6A2 mutation, p.Asp215Asn, absent in a large number of control individuals, including control individuals of Iranian ancestry, was identified in both affected siblings. COL6A2 was shown to be expressed in the human cerebral cortex and muscle biopsy revealed no specific histochemical pathology. We conclude that the COL6A2 p.Asp215Asn mutation is likely to be responsible for PME in this family; however, additional studies are warranted to further establish the pathogenic role of both COL6A2 and the extracellular proteolysis system in the pathogenesis of PME.
KeywordsMuscular Dystrophy Exome Sequencing Piracetam Human Cerebral Cortex Congenital Muscular Dystrophy
The authors would like to thank the patients and their relatives for their participation in this study. The authors also thank the Department of Neurology and the Friedman Brain Institute at the Mount Sinai School of Medicine for support (C.P-R).
Conflict of interest
The authors declare that they have no conflict of interest.
- Bassuk AG, Wallace RH, Buhr A, Buller AR, Afawi Z, Shimojo M, Miyata S, Chen S, Gonzalez-Alegre P, Griesbach HL, Wu S, Nashelsky M, Vladar EK, Antic D, Ferguson PJ, Cirak S, Voit T, Scott MP, Axelrod JD, Gurnett C, Daoud AS, Kivity S, Neufeld MY, Mazarib A, Straussberg R, Walid S, Korczyn AD, Slusarski DC, Berkovic SF, El-Shanti HI (2008) A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome. Am J Hum Genet 83:572–581PubMedCrossRefGoogle Scholar
- Corbett MA, Schwake M, Bahlo M, Dibbens LM, Lin M, Gandolfo LC, Vears DF, O’Sullivan JD, Robertson T, Bayly MA, Gardner AE, Vlaar AM, Korenke GC, Bloem BR, de Coo IF, Verhagen JM, Lehesjoki AE, Gecz J, Berkovic SF (2011) A mutation in the Golgi Qb-SNARE gene GOSR2 causes progressive myoclonus epilepsy with early ataxia. Am J Hum Genet 88:657–663PubMedCrossRefGoogle Scholar
- DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, Philippakis AA, del Angel G, Rivas MA, Hanna M, McKenna A, Fennell TJ, Kernytsky AM, Sivachenko AY, Cibulskis K, Gabriel SB, Altshuler D, Daly MJ (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43:491–498PubMedCrossRefGoogle Scholar
- Exome Variant Server (2012) NHLBI Exome Sequencing Project (ESP), Seattle, WA. URL: http://evs.gs.washington.edu/EVS/
- Joensuu T, Kuronen M, Alakurtti K, Tegelberg S, Hakala P, Aalto A, Huopaniemi L, Aula N, Michellucci R, Eriksson K, Lehesjoki AE (2007) Cystatin B: mutation detection, alternative splicing and expression in progressive myclonus epilepsy of Unverricht-Lundborg type (EPM1) patients. Eur J Hum Genet 15:185–193PubMedCrossRefGoogle Scholar
- Marti-Masso JF, Ruiz-Martinez J, Makarov V, Lopez de Munain A, Gorostidi A, Bergareche A, Yoon S, Buxbaum JD, Paisan-Ruiz C (2012) Exome sequencing identifies GCDH (glutaryl-CoA dehydrogenase) mutations as a cause of a progressive form of early-onset generalized dystonia. Hum Genet 131:435–442PubMedCrossRefGoogle Scholar
- Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047PubMedCrossRefGoogle Scholar
- Royer-Zemmour B, Ponsole-Lenfant M, Gara H, Roll P, Leveque C, Massacrier A, Ferracci G, Cillario J, Robaglia-Schlupp A, Vincentelli R, Cau P, Szepetowski P (2008) Epileptic and developmental disorders of the speech cortex: ligand/receptor interaction of wild-type and mutant SRPX2 with the plasminogen activator receptor uPAR. Hum Mol Genet 17:3617–3630PubMedCrossRefGoogle Scholar
- Rubboli G, Franceschetti S, Berkovic SF, Canafoglia L, Gambardella A, Dibbens LM, Riguzzi P, Campieri C, Magaudda A, Tassinari CA, Michelucci R (2011) Clinical and neurophysiologic features of progressive myoclonus epilepsy without renal failure caused by SCARB2 mutations. Epilepsia 52:2356–2363PubMedCrossRefGoogle Scholar