Details

Autor(en) / Beteiligte

• Damiano, John A
• Afawi, Zaid
• Bahlo, Melanie
• Mauermann, Monika
• Misk, Adel
• Arsov, Todor
• Oliver, Karen L
• Dahl, Hans-Henrik M
• Shearer, A Eliot
• Smith, Richard J H
• Hall, Nathan E
• Mahmood, Khalid
• Leventer, Richard J
• Scheffer, Ingrid E
• Muona, Mikko
• Lehesjoki, Anna-Elina
• Korczyn, Amos D
• Herrmann, Harald
• Berkovic, Samuel F
• Hildebrand, Michael S

Titel

Mutation of the nuclear lamin gene LMNB2 in progressive myoclonus epilepsy with early ataxia

Ist Teil von

• Human molecular genetics, 2015-08, Vol.24 (16), p.4483-4490

Ort / Verlag

England: Oxford University Press

Erscheinungsjahr

2015

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• 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. The p.His157Tyr mutation is located in an evolutionarily highly conserved region of the alpha-helical rod of the lamin B2 protein. 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 aetiology of PMEs to include dysfunction in nuclear lamin proteins.