title: Familial cortical myoclonus with a mutation in NOL3.
abstract: OBJECTIVE
  Myoclonus is characterized by sudden, brief involuntary movements, and its presence is debilitating. We identified a family suffering from adult onset, cortical myoclonus without associated seizures. We performed clinical, electrophysiological, and genetic studies to define this phenotype.
  
  
  METHODS
  A large, 4-generation family with a history of myoclonus underwent careful questioning, examination, and electrophysiological testing. Thirty-five family members donated blood samples for genetic analysis, which included single nucleotide polymorphism mapping, microsatellite linkage, targeted massively parallel sequencing, and Sanger sequencing. In silico and in vitro experiments were performed to investigate functional significance of the mutation.
  
  
  RESULTS
  We identified 11 members of a Canadian Mennonite family suffering from adult onset, slowly progressive, disabling, multifocal myoclonus. Somatosensory evoked potentials indicated a cortical origin of the myoclonus. There were no associated seizures. Some severely affected individuals developed signs of progressive cerebellar ataxia of variable severity late in the course of their illness. The phenotype was inherited in an autosomal dominant fashion. We demonstrated linkage to chromosome 16q21-22.1. We then sequenced all coding sequence in the critical region, identifying only a single cosegregating, novel, nonsynonymous mutation, which resides in the gene NOL3. Furthermore, this mutation was found to alter post-translational modification of NOL3 protein in vitro.
  
  
  CONCLUSIONS
  We propose that familial cortical myoclonus is a novel movement disorder that may be caused by mutation in NOL3. Further investigation of the role of NOL3 in neuronal physiology may shed light on neuronal membrane hyperexcitability and pathophysiology of myoclonus and related disorders.
authors.affiliation: Department of Neurology, School of Medicine, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jonathan F
authors.initials: JF
authors.lastname: Russell
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Steckley
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.forename: Angelika F G
authors.initials: AF
authors.lastname: Hahn
authors.forename: MacKenzie A
authors.initials: MA
authors.lastname: Howard
authors.forename: Zachary
authors.initials: Z
authors.lastname: Kornberg
authors.forename: Alden
authors.initials: A
authors.lastname: Huang
authors.forename: Seyed M
authors.initials: SM
authors.lastname: Mirsattari
authors.forename: Barry
authors.initials: B
authors.lastname: Merriman
authors.forename: Eric
authors.initials: E
authors.lastname: Klein
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.forename: Hsien-Yang
authors.initials: HY
authors.lastname: Lee
authors.forename: Andrew
authors.initials: A
authors.lastname: Kirk
authors.forename: Carol
authors.initials: C
authors.lastname: Nelson-Williams
authors.forename: Gillian
authors.initials: G
authors.lastname: Gibson
authors.forename: Scott C
authors.initials: SC
authors.lastname: Baraban
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.forename: Ying-Hui
authors.initials: YH
authors.lastname: Fu
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ptáček
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002170:Canada; D002461:Cell Line, Transformed; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16; D004569:Electroencephalography; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009207:Myoclonus / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D011392:Proline / Q000235:genetics; D014162:Transfection
chemical_list: D051017:Apoptosis Regulatory Proteins; D009124:Muscle Proteins; C112246:NOL3 protein, human; D018698:Glutamic Acid; D011392:Proline