De novo missense mutations in NALCN cause developmental and intellectual impairment with hypotonia

Journal of Human Genetics
Ryoko FukaiNaomichi Matsumoto

Abstract

Three recessive mutations in the sodium leak channel, nonselective (NALCN) have been reported to cause intellectual disability and hypotonia. In addition, 14 de novo heterozygous mutations have been identified in 15 patients with arthrogryposis and neurodevelopmental impairment. Here, we report three patients with neurodevelopmental disease and hypotonia, harboring one recurrent (p.R1181Q) and two novel mutations (p.L312V and p.V1020F) occurring de novo in NALCN. Mutation p.L312 is located in the pore forming S6 region of domain I and p.V1020F in the S5 region of domain III. Mutation p.R1181Q is in a linker region. Mapping these three mutations to a model of NALCN showed p.Leu312 and p.Val1020 positioned in the hydrophobic core of the pore modules, indicating these two mutations may affect the gating function of NALCN. Although p.R1181Q is unlikely to affect the ion channel structure, previous studies have shown that an analogous mutation in Caenorhabditis elegans produced a phenotype with a coiling locomotion, suggesting that p.R1181Q could also affect NALCN function. Our three patients showed profound intellectual disability and growth delay, facial dysmorphologies and hypotonia. The present data support previous work suggest...Continue Reading

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Citations

Jul 31, 2016·Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia·Indu SivaramanRichard A Prayson
Oct 3, 2017·PLoS Genetics·Irini TopalidouMichael Ailion
Mar 8, 2019·Journal of Medical Genetics·Kazuhiro IwamaNaomichi Matsumoto
Nov 16, 2016·Annals of Clinical and Translational Neurology·Bernarda LozicHelge Boman
Dec 5, 2020·Nature Communications·Yunlu KangLei Chen
Nov 19, 2020·Nature Communications·Jiongfang XieZhen Yan

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