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

Ryoko Fukai, Hirotomo Saitsu, Nobuhiko Okamoto, Yasunari Sakai, Aviva Fattal-Valevski, Shiina Masaaki, Yukihiro Kitai, Michiko Torio, Kanako Kojima-Ishii, Kenji Ihara, Veronika Chernuha, Mitsuko Nakashima, Satoko Miyatake, Fumiaki Tanaka, Noriko Miyake, Naomichi Matsumoto

研究成果: Contribution to journalArticle査読

19 被引用数 (Scopus)


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.

ジャーナルJournal of Human Genetics
出版ステータス出版済み - 5 1 2016

All Science Journal Classification (ASJC) codes

  • 遺伝学
  • 遺伝学(臨床)


「De novo missense mutations in NALCN cause developmental and intellectual impairment with hypotonia」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。