title: A Gain-of-Function Mutation in NALCN in a Child with Intellectual Disability, Ataxia, and Arthrogryposis.
abstract: NALCN and its homologues code for the ion channel responsible for half of background Na(+) -leak conductance in vertebrate and invertebrate neurons. Recessive mutations in human NALCN cause intellectual disability (ID) with hypotonia. Here, we report a de novo heterozygous mutation in NALCN affecting a conserved residue (p.R1181Q) in a girl with ID, episodic and persistent ataxia, and arthrogryposis. Interestingly, her episodes of ataxia were abolished by the administration of acetazolamide, similar to the response observed in episodic ataxia associated with other ion channels. Introducing the analogous mutation in the Caenorhabditis elegans homologue nca-1 induced a coiling locomotion phenotype, identical to that obtained with previously characterized C. elegans gain-of-function nca alleles, suggesting that p.R1181Q confers the same property to NALCN. This observation thus suggests that dominant mutations in NALCN can cause a neurodevelopmental phenotype that overlaps with, while being mostly distinct from that associated with recessive mutations in the same gene.
authors: Department of Biochemistry, Kyorin University School of Medicine, Tokyo, Japan.
authors: Kyota
authors: K
authors: Aoyagi
authors: CHU Sainte-Justine Research Center, Montreal, Canada.|Department of Neurosciences, University of Montreal, Montreal, Canada.|Department of Pediatrics, University of Montreal, Montreal, Canada.
authors: Elsa
authors: E
authors: Rossignol
authors: CHU Sainte-Justine Research Center, Montreal, Canada.
authors: Fadi F
authors: FF
authors: Hamdan
authors: Lunenfeld-Tanenbaum Research Institute and Institute of Medical Science, Department of Molecular Genetics, University of Toronto, Ontario, Canada.
authors: Ben
authors: B
authors: Mulcahy
authors: Lunenfeld-Tanenbaum Research Institute and Institute of Medical Science, Department of Molecular Genetics, University of Toronto, Ontario, Canada.
authors: Lin
authors: L
authors: Xie
authors: Department of Biochemistry, Kyorin University School of Medicine, Tokyo, Japan.
authors: Shinya
authors: S
authors: Nagamatsu
authors: Montreal Neurological Institute, McGill University, Montreal, Canada.
authors: Guy A
authors: GA
authors: Rouleau
authors: Lunenfeld-Tanenbaum Research Institute and Institute of Medical Science, Department of Molecular Genetics, University of Toronto, Ontario, Canada.
authors: Mei
authors: M
authors: Zhen
authors: CHU Sainte-Justine Research Center, Montreal, Canada.|Department of Neurosciences, University of Montreal, Montreal, Canada.|Department of Pediatrics, University of Montreal, Montreal, Canada.
authors: Jacques L
authors: JL
authors: Michaud
mesh_terms: D000086:Acetazolamide / Q000627:therapeutic use; D000818:Animals; D001176:Arthrogryposis / Q000235:genetics* / Q000378:metabolism; D001259:Ataxia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics; D008565:Membrane Proteins; D009154:Mutation; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D007473:Ion Channels; D008565:Membrane Proteins; C544681:NALCN protein, human; D015222:Sodium Channels; C525141:unc-77 protein, C elegans; D000086:Acetazolamide
keywords: C. elegans; NALCN; Na+-leak; de novo; gain-of-function