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Identification of COL6A2 mutations in progressive myoclonus epilepsy syndrome

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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.

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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
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  2. Catharine E. Krebs
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  3. Vladimir Makarov
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  6. Hossein Darvish
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  7. Steven Frucht
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  8. Gholam Ali Shahidi
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  9. Joseph D. Buxbaum
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  10. Coro Paisán-Ruiz
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Corresponding author

Correspondence to Coro Paisán-Ruiz.

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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.

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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

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

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