title: Mutation of the nuclear lamin gene LMNB2 in progressive myoclonus epilepsy with early ataxia.
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.
authors.affiliation: Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, VIC, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Damiano
authors.affiliation: Sackler School of Medicine, Tel Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Afawi
authors.affiliation: Bioinformatics Division, The Walter and Eliza Hall Institute, Melbourne, VIC, Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.affiliation: Division of Molecular Genetics, German Cancer Research Centre, Heidelberg, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Mauermann
authors.affiliation: Department of Neurology, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Adel
authors.initials: A
authors.lastname: Misk
authors.affiliation: Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, VIC, Australia.
authors.forename: Todor
authors.initials: T
authors.lastname: Arsov
authors.affiliation: Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, VIC, Australia.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Oliver
authors.affiliation: Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, VIC, Australia.
authors.forename: Hans-Henrik M
authors.initials: HH
authors.lastname: Dahl
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Molecular Otolaryngology and Renal Research Laboratories, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
authors.forename: A Eliot
authors.initials: AE
authors.lastname: Shearer
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Molecular Otolaryngology and Renal Research Laboratories, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.affiliation: Life Sciences Computation Centre, VLSCI, Melbourne, VIC, Australia, La Trobe Institute for Molecular Sciences, La Trobe University, Melbourne, VIC, Australia.
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Hall
authors.affiliation: Life Sciences Computation Centre, VLSCI, Melbourne, VIC, Australia.
authors.forename: Khalid
authors.initials: K
authors.lastname: Mahmood
authors.affiliation: 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.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Leventer
authors.affiliation: 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.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: Institute for Molecular Medicine, Neuroscience Centre and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland and Folkhålsan Institute of Genetics, Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Muona
authors.affiliation: Institute for Molecular Medicine, Neuroscience Centre and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland and Folkhålsan Institute of Genetics, Helsinki, Finland.
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
authors.affiliation: Sackler School of Medicine, Tel Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel.
authors.forename: Amos D
authors.initials: AD
authors.lastname: Korczyn
authors.affiliation: Division of Molecular Genetics, German Cancer Research Centre, Heidelberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Herrmann
authors.affiliation: Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, VIC, Australia.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.affiliation: Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, VIC, Australia, michael.hildebrand@unimelb.edu.au.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hildebrand
mesh_terms: D019943:Amino Acid Substitution; D001259:Ataxia / Q000235:genetics*; D002648:Child; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D004831:Epilepsies, Myoclonic / Q000235:genetics*; D005190:Family; D005260:Female; D006801:Humans; D034921:Lamin Type B / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense
chemical_list: D034921:Lamin Type B