title: De novo missense mutations in NALCN cause developmental and intellectual impairment with hypotonia.
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.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.|Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Fukai
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Hirotomo
authors.identifier: http://orcid.org/0000-0003-0723-0960
authors.initials: H
authors.lastname: Saitsu
authors.affiliation: Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Okamoto
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Pediatric Neurology Unit, Tel Aviv Sourasky Medical Centre, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Aviva
authors.initials: A
authors.lastname: Fattal-Valevski
authors.affiliation: Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Shiina
authors.initials: S
authors.lastname: Masaaki
authors.affiliation: Department of Pediatric Neurology, Morinomiya Hospital, Osaka, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Kitai
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Torio
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Kojima-Ishii
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.|Department of Pediatrics, Faculty of Medicine, Oita University, Yufu, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ihara
authors.affiliation: Pediatric Neurology Unit, Tel Aviv Sourasky Medical Centre, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Veronika
authors.initials: V
authors.lastname: Chernuha
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Miyatake
authors.affiliation: Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
mesh_terms: D000483:Alleles; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D007473:Ion Channels; D008297:Male; D008565:Membrane Proteins; D008958:Models, Molecular; D009123:Muscle Hypotonia / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D011487:Protein Conformation; D017422:Sequence Analysis, DNA; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics*; D013577:Syndrome
chemical_list: D007473:Ion Channels; D008565:Membrane Proteins; C544681:NALCN protein, human; D015222:Sodium Channels