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

Hum Mol Genet. 2015 Aug 15;24(16):4483-90. doi: 10.1093/hmg/ddv171.

John A Damiano ¹, Zaid Afawi ², Melanie Bahlo ³, Monika Mauermann ⁴, Adel Misk ⁵, Todor Arsov ¹, Karen L Oliver ¹, Hans-Henrik M Dahl ¹, A Eliot Shearer ⁶, Richard J H Smith ⁶, Nathan E Hall ⁷, Khalid Mahmood ⁸, Richard J Leventer ⁹, Ingrid E Scheffer ¹⁰, Mikko Muona ¹¹, Anna-Elina Lehesjoki ¹¹, Amos D Korczyn ², Harald Herrmann ⁴, Samuel F Berkovic ¹, Michael S Hildebrand ¹²

Affiliations

1 Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, VIC, Australia.
2 Sackler School of Medicine, Tel Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel.
3 Bioinformatics Division, The Walter and Eliza Hall Institute, Melbourne, VIC, Australia.
4 Division of Molecular Genetics, German Cancer Research Centre, Heidelberg, Germany.
5 Department of Neurology, Shaare Zedek Medical Center, Jerusalem, Israel.
6 Department of Otolaryngology-Head and Neck Surgery, Molecular Otolaryngology and Renal Research Laboratories, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
7 Life Sciences Computation Centre, VLSCI, Melbourne, VIC, Australia, La Trobe Institute for Molecular Sciences, La Trobe University, Melbourne, VIC, Australia.
8 Life Sciences Computation Centre, VLSCI, Melbourne, VIC, Australia.
9 Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, VIC, Australia, Murdoch Children's Research Institute, Melbourne, VIC, Australia, Department of Neurology, Royal Children's Hospital, Melbourne, VIC, Australia.
10 Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, VIC, Australia, Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, VIC, Australia, The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia.
11 Institute for Molecular Medicine, Neuroscience Centre and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland and Folkhålsan Institute of Genetics, Helsinki, Finland.
12 Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, VIC, Australia, michael.hildebrand@unimelb.edu.au.

PMID: 25954030 DOI: 10.1093/hmg/ddv171

Abstract

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.

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