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

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

doi:10.1093/hmg/ddv171

Back

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

Journal article

Open access

Peer reviewed

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

John A Damiano, Zaid Afawi, Melanie Bahlo, Monika Mauermann, Adel Misk, Todor Arsov, Karen L Oliver, Hans-Henrik M Dahl, A Eliot Shearer, Richard J H Smith, …

Human molecular genetics, Vol.24(16), pp.4483-4490

08/15/2015

DOI: 10.1093/hmg/ddv171

PMCID: PMC6281347

PMID: 25954030

Files and links (1)

url

https://doi.org/10.1093/hmg/ddv171View

Published (Version of record) Open Access

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.

Chromosomes, Human, Pair 19 - genetics

Lamin Type B - genetics

Humans

Family

Female

Male

Mutation, Missense

Ataxia - genetics

Child

Amino Acid Substitution

Epilepsies, Myoclonic - genetics

Details

Title: Subtitle: Mutation of the nuclear lamin gene LMNB2 in progressive myoclonus epilepsy with early ataxia
Creators: John A Damiano - Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, VIC, Australia
Zaid Afawi - Sackler School of Medicine, Tel Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel
Melanie Bahlo - Bioinformatics Division, The Walter and Eliza Hall Institute, Melbourne, VIC, Australia
Monika Mauermann - Division of Molecular Genetics, German Cancer Research Centre, Heidelberg, Germany
Adel Misk - Department of Neurology, Shaare Zedek Medical Center, Jerusalem, Israel
Todor Arsov - Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, VIC, Australia
Karen L Oliver - Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, VIC, Australia
Hans-Henrik M Dahl - Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, VIC, Australia
A Eliot Shearer - Department of Otolaryngology-Head and Neck Surgery, Molecular Otolaryngology and Renal Research Laboratories, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
Richard J H Smith - Department of Otolaryngology-Head and Neck Surgery, Molecular Otolaryngology and Renal Research Laboratories, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
Nathan E Hall - Life Sciences Computation Centre, VLSCI, Melbourne, VIC, Australia, La Trobe Institute for Molecular Sciences, La Trobe University, Melbourne, VIC, Australia
Khalid Mahmood - Life Sciences Computation Centre, VLSCI, Melbourne, VIC, Australia
Richard J Leventer - 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
Ingrid E Scheffer - 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
Mikko Muona - Institute for Molecular Medicine, Neuroscience Centre and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland and Folkhålsan Institute of Genetics, Helsinki, Finland
Anna-Elina Lehesjoki - Institute for Molecular Medicine, Neuroscience Centre and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland and Folkhålsan Institute of Genetics, Helsinki, Finland
Amos D Korczyn - Sackler School of Medicine, Tel Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel
Harald Herrmann - Division of Molecular Genetics, German Cancer Research Centre, Heidelberg, Germany
Samuel F Berkovic - Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, VIC, Australia
Michael S Hildebrand - Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, VIC, Australia, michael.hildebrand@unimelb.edu.au
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.24(16), pp.4483-4490
DOI: 10.1093/hmg/ddv171
PMID: 25954030
PMCID: PMC6281347
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: England
Language: English
Date published: 08/15/2015
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
Record Identifier: 9984006357902771

Metrics

18 Record Views

41 Times Cited - Web of Science