title: Identification of COL6A2 mutations in progressive myoclonus epilepsy syndrome.
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.
authors.affiliation: Movement Disorders Clinic, Hazrat Rasool Hospital, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Siamak
authors.initials: S
authors.lastname: Karkheiran
authors.forename: Catharine E
authors.initials: CE
authors.lastname: Krebs
authors.forename: Vladimir
authors.initials: V
authors.lastname: Makarov
authors.forename: Yalda
authors.initials: Y
authors.lastname: Nilipour
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hubert
authors.forename: Hossein
authors.initials: H
authors.lastname: Darvish
authors.forename: Steven
authors.initials: S
authors.lastname: Frucht
authors.forename: Gholam Ali
authors.initials: GA
authors.lastname: Shahidi
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Coro
authors.initials: C
authors.lastname: Paisán-Ruiz
mesh_terms: D000293:Adolescent; D000328:Adult; D001216:Asparagine; D001224:Aspartic Acid; D002540:Cerebral Cortex / Q000378:metabolism*; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D024142:Collagen Type VI / Q000235:genetics* / Q000378:metabolism; D003241:Consanguinity; D004569:Electroencephalography; D005260:Female; D006720:Homozygote; D006801:Humans; D007492:Iran; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D013577:Syndrome
chemical_list: C504344:COL6A2 protein, human; D024142:Collagen Type VI; D001224:Aspartic Acid; D001216:Asparagine