A Gain-of-Function Mutation in NALCN in a Child with Intellectual Disability, Ataxia, and Arthrogryposis

作者：Aoyagi Kyota; Rossignol Elsa; Hamdan Fadi F; Mulcahy Ben; Xie Lin; Nagamatsu Shinya; Rouleau Guy A; Zhen Mei; Michaud Jacques L^*

来源：Human Mutation, 2015, 36(8): 753-757.

DOI：10.1002/humu.22797

• NALCN
• de novo
• gain-of-function
• C
• elegans
• Na+-leak

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.

• 出版日期2015-8
• 单位河北医科大学; McGill