Skip to main content

Advertisement

Springer Nature Link
Log in

Identification of COL6A2 mutations in progressive myoclonus epilepsy syndrome

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • 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 83:572–581

    Article  PubMed  CAS  Google Scholar 

  • Bennett VD, Adams SL (1990) Identification of a cartilage-specific promoter within intron 2 of the chick alpha 2(I) collagen gene. J Biol Chem 265:2223–2230

    PubMed  CAS  Google Scholar 

  • Berkovic SF, Andermann F, Carpenter S, Wolfe LS (1986) Progressive myoclonus epilepsies: specific causes and diagnosis. N Engl J Med 315:296–305

    Article  PubMed  CAS  Google Scholar 

  • Bonnemann CG (2011) The collagen VI-related myopathies: muscle meets its matrix. Nat Rev Neurol 7:379–390

    Article  PubMed  Google Scholar 

  • Camacho Vanegas O, Bertini E, Zhang RZ, Petrini S, Minosse C, Sabatelli P, Giusti B, Chu ML, Pepe G (2001) Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI. Proc Natl Acad Sci USA 98:7516–7521

    Article  PubMed  CAS  Google Scholar 

  • Caviness JN, Brown P (2004) Myoclonus: current concepts and recent advances. Lancet Neurol 3:598–607

    Article  PubMed  Google Scholar 

  • Cheng JS, Dubal DB, Kim DH, Legleiter J, Cheng IH, Yu GQ, Tesseur I, Wyss-Coray T, Bonaldo P, Mucke L (2009) Collagen VI protects neurons against Abeta toxicity. Nat Neurosci 12:119–121

    Article  PubMed  CAS  Google Scholar 

  • Cheng IH, Lin YC, Hwang E, Huang HT, Chang WH, Liu YL, Chao CY (2011) Collagen VI protects against neuronal apoptosis elicited by ultraviolet irradiation via an Akt/phosphatidylinositol 3-kinase signaling pathway. Neuroscience 183:178–188

    Article  PubMed  CAS  Google 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 88:657–663

    Article  PubMed  CAS  Google 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 43:491–498

    Article  PubMed  CAS  Google Scholar 

  • Exome Variant Server (2012) NHLBI Exome Sequencing Project (ESP), Seattle, WA. URL: http://evs.gs.washington.edu/EVS/

  • Fox MA (2008) Novel roles for collagens in wiring the vertebrate nervous system. Curr Opin Cell Biol 20:508–513

    Article  PubMed  CAS  Google Scholar 

  • Grossman TR, Gamliel A, Wessells RJ, Taghli-Lamallem O, Jepsen K, Ocorr K, Korenberg JR, Peterson KL, Rosenfeld MG, Bodmer R, Bier E (2011) Over-expression of DSCAM and COL6A2 cooperatively generates congenital heart defects. PLoS Genet 7:e1002344

    Article  PubMed  CAS  Google Scholar 

  • Hubert T, Grimal S, Carroll P, Fichard-Carroll A (2009) Collagens in the developing and diseased nervous system. Cell Mol Life Sci 66:1223–1238

    Article  PubMed  CAS  Google Scholar 

  • Jobsis GJ, Boers JM, Barth PG, de Visser M (1999) Bethlem myopathy: a slowly progressive congenital muscular dystrophy with contractures. Brain 122(Pt 4):649–655

    Article  PubMed  Google Scholar 

  • 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 15:185–193

    Article  PubMed  CAS  Google Scholar 

  • Kim HS, Yim SV, Jung KH, Zheng LT, Kim YH, Lee KH, Chung SY, Rha HK (2007) Altered DNA copy number in patients with different seizure disorder type: by array-CGH. Brain Dev 29:639–643

    Article  PubMed  Google Scholar 

  • Klewer SE, Krob SL, Kolker SJ, Kitten GT (1998) Expression of type VI collagen in the developing mouse heart. Dev Dyn 211:248–255

    Article  PubMed  CAS  Google Scholar 

  • Krebs CE, Paisan-Ruiz C (2012) The use of next-generation sequencing in movement disorders. Front Genet 3:75

    PubMed  Google Scholar 

  • Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754–1760

    Article  PubMed  CAS  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408

    Article  PubMed  CAS  Google Scholar 

  • Makarov V, O’Grady T, Cai G, Lihm J, Buxbaum JD, Yoon S (2011) AnnTools: a comprehensive and versatile annotation toolkit for genomic variants. Bioinformatics 28:724–725

    Article  Google 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 131:435–442

    Article  PubMed  CAS  Google Scholar 

  • Mercuri E, Yuva Y, Brown SC, Brockington M, Kinali M, Jungbluth H, Feng L, Sewry CA, Muntoni F (2002) Collagen VI involvement in Ullrich syndrome: a clinical, genetic, and immunohistochemical study. Neurology 58:1354–1359

    Article  PubMed  CAS  Google Scholar 

  • Merlini L, Martoni E, Grumati P, Sabatelli P, Squarzoni S, Urciuolo A, Ferlini A, Gualandi F, Bonaldo P (2008) Autosomal recessive myosclerosis myopathy is a collagen VI disorder. Neurology 71:1245–1253

    Article  PubMed  CAS  Google Scholar 

  • Nishimura I, Muragaki Y, Olsen BR (1989) Tissue-specific forms of type IX collagen-proteoglycan arise from the use of two widely separated promoters. J Biol Chem 264:20033–20041

    PubMed  CAS  Google Scholar 

  • Paisan-Ruiz C, Scopes G, Lee P, Houlden H (2009) Homozygosity mapping through whole genome analysis identifies a COL18A1 mutation in an Indian family presenting with an autosomal recessive neurological disorder. Am J Med Genet B Neuropsychiatr Genet 150B:993–997

    Article  PubMed  CAS  Google 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 276:2045–2047

    Article  PubMed  CAS  Google Scholar 

  • Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575

    Article  PubMed  CAS  Google Scholar 

  • Quinlan AR, Hall IM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26:841–842

    Article  PubMed  CAS  Google Scholar 

  • Ramachandran N, Girard JM, Turnbull J, Minassian BA (2009) The autosomal recessively inherited progressive myoclonus epilepsies and their genes. Epilepsia 50(Suppl 5):29–36

    Article  PubMed  CAS  Google 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 17:3617–3630

    Article  PubMed  CAS  Google 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 52:2356–2363

    Article  PubMed  CAS  Google Scholar 

  • Saitta B, Chu ML (1994) Two promoters control the transcription of the human alpha 2(VI) collagen gene. Eur J Biochem 223:675–682

    Article  PubMed  CAS  Google Scholar 

  • Shahwan A, Farrell M, Delanty N (2005) Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol 4:239–248

    Article  PubMed  CAS  Google Scholar 

  • Suelves M, Vidal B, Serrano AL, Tjwa M, Roma J, Lopez-Alemany R, Luttun A, de Lagran MM, Diaz-Ramos A, Jardi M, Roig M, Dierssen M, Dewerchin M, Carmeliet P, Munoz-Canoves P (2007) uPA deficiency exacerbates muscular dystrophy in MDX mice. J Cell Biol 178:1039–1051

    Article  PubMed  CAS  Google Scholar 

  • Thusberg J, Olatubosun A, Vihinen M (2011) Performance of mutation pathogenicity prediction methods on missense variants. Hum Mutat 32:358–368

    Article  PubMed  Google Scholar 

  • Tsao CY, Mendell JR (2006) Coexisting muscular dystrophies and epilepsy in children. J Child Neurol 21:148–150

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

  1. Movement Disorders Clinic, Hazrat Rasool Hospital, Tehran University of Medical Sciences, Tehran, Iran

    Siamak Karkheiran & Gholam Ali Shahidi

  2. Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1137, New York, USA

    Catharine E. Krebs, Benjamin Hubert, Steven Frucht & Coro Paisán-Ruiz

  3. The Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, USA

    Vladimir Makarov & Joseph D. Buxbaum

  4. Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, USA

    Vladimir Makarov, Joseph D. Buxbaum & Coro Paisán-Ruiz

  5. Department of Pathology, Myopathology Lab, Toos Hospital, Tehran, Iran

    Yalda Nilipour

  6. Department of Clinical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Hossein Darvish

  7. Friedman Brain Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, USA

    Steven Frucht, Joseph D. Buxbaum & Coro Paisán-Ruiz

  8. Department of Neurology, Hazrat Rasool Hospital, Tehran University of Medical Sciences, Tehran, Iran

    Gholam Ali Shahidi

  9. Department of Neuroscience, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, USA

    Joseph D. Buxbaum

  10. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, USA

    Joseph D. Buxbaum & Coro Paisán-Ruiz

Authors
  1. Siamak Karkheiran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Catharine E. Krebs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vladimir Makarov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yalda Nilipour
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Benjamin Hubert
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hossein Darvish
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Steven Frucht
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gholam Ali Shahidi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Joseph D. Buxbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Coro Paisán-Ruiz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Coro Paisán-Ruiz.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (TIFF 577 kb)

Supplementary material 1: A) H&E stain; Normal fibers size variation with no dystrophic or myopathic change. B) Gömöri trichrome stain; No ragged-red fiber. C) NADH-TR reaction; Good differentiation of muscle fibers with regular intermyofibrillar network. D) ATPase PH 4.35; Normal checkerboard pattern.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Karkheiran, S., Krebs, C.E., Makarov, V. et al. Identification of COL6A2 mutations in progressive myoclonus epilepsy syndrome. Hum Genet 132, 275–283 (2013). https://doi.org/10.1007/s00439-012-1248-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-012-1248-1

Keywords

Search

Navigation