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

被引:27
作者
Fukai, Ryoko [1 ,2 ]
Saitsu, Hirotomo [1 ]
Okamoto, Nobuhiko [3 ,4 ]
Sakai, Yasunari [5 ]
Fattal-Valevski, Aviva [6 ]
Masaaki, Shiina [7 ]
Kitai, Yukihiro [8 ]
Torio, Michiko [5 ]
Kojima-Ishii, Kanako [5 ]
Ihara, Kenji [5 ,9 ]
Chernuha, Veronika [6 ]
Nakashima, Mitsuko [1 ]
Miyatake, Satoko [1 ]
Tanaka, Fumiaki [2 ]
Miyake, Noriko [1 ]
Matsumoto, Naomichi [1 ]
机构
[1] Yokohama City Univ, Grad Sch Med, Dept Human Genet, Yokohama, Kanagawa 2360004, Japan
[2] Yokohama City Univ, Grad Sch Med, Dept Neurol & Stroke Med, Yokohama, Kanagawa 2360004, Japan
[3] Osaka Med Ctr, Dept Med Genet, Izumi, Japan
[4] Res Inst Maternal & Child Hlth, Izumi, Japan
[5] Kyushu Univ, Grad Sch Med Sci, Dept Pediat, Fukuoka 812, Japan
[6] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Sackler Fac Med, Pediat Neurol Unit, IL-69978 Tel Aviv, Israel
[7] Yokohama City Univ, Grad Sch Med, Dept Biochem, Yokohama, Kanagawa 2360004, Japan
[8] Morinomiya Hosp, Dept Pediat Neurol, Osaka, Japan
[9] Oita Univ, Fac Med, Dept Pediat, Yufu, Japan
基金
日本科学技术振兴机构; 日本学术振兴会;
关键词
VOLTAGE-GATED SODIUM; CRYSTAL-STRUCTURE; LEAK CHANNEL; EXCITABILITY; DISEASE; SERVER; DELAY;
D O I
10.1038/jhg.2015.163
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:451 / 455
页数:5
相关论文
共 19 条
[1]   A method and server for predicting damaging missense mutations [J].
Adzhubei, Ivan A. ;
Schmidt, Steffen ;
Peshkin, Leonid ;
Ramensky, Vasily E. ;
Gerasimova, Anna ;
Bork, Peer ;
Kondrashov, Alexey S. ;
Sunyaev, Shamil R. .
NATURE METHODS, 2010, 7 (04) :248-249
[2]   Mutations in NALCN Cause an Autosomal-Recessive Syndrome with Severe Hypotonia, Speech Impairment, and Cognitive Delay [J].
Al-Sayed, Moeenaldeen D. ;
Al-Zaidan, Hamad ;
Albakheet, AlBandary ;
Hakami, Hana ;
Kenana, Rosan ;
Al-Yafee, Yusra ;
Al-Dosary, Mazhor ;
Qari, Alya ;
Al-Sheddi, Tarfa ;
Al-Muheiza, Muhammed ;
Al-Qubbaj, Wafa ;
Lakmache, Yamina ;
Al-Hindi, Hindi ;
Ghaziuddin, Muhammad ;
Colak, Dilek ;
Kaya, Namik .
AMERICAN JOURNAL OF HUMAN GENETICS, 2013, 93 (04) :721-726
[3]   A Gain-of-Function Mutation in NALCN in a Child with Intellectual Disability, Ataxia, and Arthrogryposis [J].
Aoyagi, Kyota ;
Rossignol, Elsa ;
Hamdan, Fadi F. ;
Mulcahy, Ben ;
Xie, Lin ;
Nagamatsu, Shinya ;
Rouleau, Guy A. ;
Zhen, Mei ;
Michaud, Jacques L. .
HUMAN MUTATION, 2015, 36 (08) :753-757
[4]   De Novo Mutations in NALCN Cause a Syndrome Characterized by Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay [J].
Chong, Jessica X. ;
McMillin, Margaret J. ;
Shively, Kathryn M. ;
Beck, Anita E. ;
Marvin, Colby T. ;
Armenteros, Jose R. ;
Buckingham, Kati J. ;
Nkinsi, Naomi T. ;
Boyle, Evan A. ;
Berry, Margaret N. ;
Bocian, Maureen ;
Foulds, Nicola ;
Uzielli, Maria Luisa Giovannucci ;
Haldeman-Englert, Chad ;
Hennekam, Raoul C. M. ;
Kaplan, Paige ;
Kline, Antonie D. ;
Mercer, Catherine L. ;
Nowaczyk, Malgorzata J. M. ;
Wassink-Ruiter, Jolien S. Klein ;
McPherson, Elizabeth W. ;
Moreno, Regina A. ;
Scheuerle, Angela E. ;
Shashi, Vandana ;
Stevens, Cathy A. ;
Carey, John C. ;
Monteil, Arnaud ;
Lory, Philippe ;
Tabor, Holly K. ;
Smith, Joshua D. ;
Shendure, Jay ;
Nickerson, Deborah A. ;
Bamshad, Michael J. .
AMERICAN JOURNAL OF HUMAN GENETICS, 2015, 96 (03) :462-473
[5]   The sodium leak channel, NALCN, in health and disease [J].
Cochet-Bissuel, Maud ;
Lory, Philippe ;
Monteil, Arnaud .
FRONTIERS IN CELLULAR NEUROSCIENCE, 2014, 8
[6]   A case of autism spectrum disorder arising from a de novo missense mutation in POGZ [J].
Fukai, Ryoko ;
Hiraki, Yoko ;
Yofune, Hiroko ;
Tsurusaki, Yoshinori ;
Nakashima, Mitsuko ;
Saitsu, Hirotomo ;
Tanaka, Fumiaki ;
Miyake, Noriko ;
Matsumoto, Naomichi .
JOURNAL OF HUMAN GENETICS, 2015, 60 (05) :277-279
[7]   Protein structure prediction on the Web: a case study using the Phyre server [J].
Kelley, Lawrence A. ;
Sternberg, Michael J. E. .
NATURE PROTOCOLS, 2009, 4 (03) :363-371
[8]   Recessive truncating NALCN mutation in infantile neuroaxonal dystrophy with facial dysmorphism [J].
Koroglu, Cigdem ;
Seven, Mehmet ;
Tolun, Aslihan .
JOURNAL OF MEDICAL GENETICS, 2013, 50 (08) :515-520
[9]   Ligand-induced structural changes in the cyclic nucleotide-modulated potassium channel MloK1 [J].
Kowal, Julia ;
Chami, Mohamed ;
Baumgartner, Paul ;
Arheit, Marcel ;
Chiu, Po-Lin ;
Rangl, Martina ;
Scheuring, Simon ;
Schroeder, Gunnar F. ;
Nimigean, Crina M. ;
Stahlberg, Henning .
NATURE COMMUNICATIONS, 2014, 5
[10]   The neuronal channel NALCN contributes resting sodium permeability and is required for normal respiratory rhythm [J].
Lu, Boxun ;
Su, Yanhua ;
Das, Sudipto ;
Liu, Jin ;
Xia, Jingsheng ;
Ren, Dejian .
CELL, 2007, 129 (02) :371-383