Mutation of the nuclear lamin gene LMNB2 in progressive myoclonus epilepsy with early ataxia
Damiano, JA; Afawi, Z; Bahlo, M; Mauermann, M; Misk, A; Arsov, T; Oliver, KL; Dahl, HH; Shearer, AE; Smith, RJ; Hall, NE; Mahmood, K; Leventer, RJ; Scheffer, IE; Muona, M; Lehesjoki, AE; Korczyn, AD; Hermann, H; Berkovic, SF; Hildebrand, MS
Human Molecular Genetics
Journal Article in press
We studied a consanguineous Palestinian Arab family segregating an autosomal recessive progressive myoclonus epilepsy (PME) with early ataxia. PME is a rare, often fatal syndrome, initially responsive to antiepileptic drugs which over time becomes refractory, and can be associated with cognitive decline. Linkage analysis was performed and the disease locus narrowed to chromosome 19p13.3. Fourteen candidate genes were screened by conventional Sanger sequencing and in one, LMNB2, a novel homozygous missense mutation was identified that segregated with the PME in the family. Whole exome sequencing excluded other likely pathogenic coding variants in the linked interval. In vitro assembly analysis of mutant lamin B2 protein revealed a distinct defect in the assembly of the highly ordered fibrous arrays typically formed by wild-type lamin B2. Our data suggests that disruption of the organisation of the nuclear lamina in neurons, perhaps through abnormal neuronal migration, causes the epilepsy and early ataxia syndrome, and extends the etiology of PMEs to include dysfunction in nuclear lamin proteins.