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 suggesting heterozygous NALCN mutations lead to syndromic neurodevelopmental impairment.
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Acknowledgements
We thank the patients and their families for participating in this work. We were supported in part by a grant for Research on Measures for Intractable Diseases, a grant for Comprehensive Research on Disability Health and Welfare, the Strategic Research Program for Brain Science (SRPBS) and a grant for Initiative on Rare and Undiagnosed Diseases in Pediatrics (IRUD-P) from the Japan Agency for Medical Research and Development (AMED); a Grant-in-Aid for Scientific Research on Innovative Areas (Transcription Cycle) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT); Grants-in-Aid for Scientific Research (A, B, and C), and challenging Exploratory Research from the Japan Society for the Promotion of Science (JSPS); the fund for Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems from the Japan Science and Technology Agency (JST); the Takeda Science Foundation; the Yokohama Foundation for Advancement of Medical Science; and the Hayashi Memorial Foundation for Female Natural Scientists.
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Fukai, R., Saitsu, H., Okamoto, N. et al. De novo missense mutations in NALCN cause developmental and intellectual impairment with hypotonia. J Hum Genet 61, 451–455 (2016). https://doi.org/10.1038/jhg.2015.163
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DOI: https://doi.org/10.1038/jhg.2015.163
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