TY - JOUR
T1 - Erbb4 mutations that disrupt the neuregulin-erbb4 pathway cause amyotrophic lateral sclerosis type 19
AU - Takahashi, Yuji
AU - Fukuda, Yoko
AU - Yoshimura, Jun
AU - Toyoda, Atsushi
AU - Kurppa, Kari
AU - Moritoyo, Hiroyoko
AU - Belzil, Veronique V.
AU - Dion, Patrick A.
AU - Higasa, Koichiro
AU - Doi, Koichiro
AU - Ishiura, Hiroyuki
AU - Mitsui, Jun
AU - Date, Hidetoshi
AU - Ahsan, Budrul
AU - Matsukawa, Takashi
AU - Ichikawa, Yaeko
AU - Moritoyo, Takashi
AU - Ikoma, Mayumi
AU - Hashimoto, Tsukasa
AU - Kimura, Fumiharu
AU - Murayama, Shigeo
AU - Onodera, Osamu
AU - Nishizawa, Masatoyo
AU - Yoshida, Mari
AU - Atsuta, Naoki
AU - Sobue, Gen
AU - Cals, Ja
AU - Fifita, Jennifer A.
AU - Williams, Kelly L.
AU - Blair, Ian P.
AU - Nicholson, Garth A.
AU - Gonzalez-Perez, Paloma
AU - Brown, Robert H.
AU - Nomoto, Masahiro
AU - Elenius, Klaus
AU - Rouleau, Guy A.
AU - Fujiyama, Asao
AU - Morishita, Shinichi
AU - Goto, Jun
AU - Tsuji, Shoji
N1 - Funding Information:
We thank all the family members for participating in this study. This study was supported in part by KAKENHI (Grants-in-Aid for Scientific Research on Innovative Areas [22129001 and 22129002]) to S.T.; the Global COE Program from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and a grant-in-aid (H23-Jitsuyoka [Nanbyo]-Ippan-004) from the Ministry of Health, Labour, and Welfare, Japan to S.T. We acknowledge support to R.H.B. from ALS Therapy Alliance, Project ALS, P2ALS, the Angel Fund, the Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel ALS Research Foundation, the ALS Family Charitable Foundation, and grant 1R01NS050557 from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health and support to G.A.N. from the MND Research Institute of Australia. P.G.-P. was supported by the Alfonso Martin Escudero Foundation (Madrid).
PY - 2013/11/7
Y1 - 2013/11/7
N2 - Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder characterized by the degeneration of motor neurons and typically results in death within 3-5 years from onset. Familial ALS (FALS) comprises 5%-10% of ALS cases, and the identification of genes associated with FALS is indispensable to elucidating the molecular pathogenesis.We identified a Japanese family affected by late-onset, autosomal-dominant ALS in which mutations in genes known to be associated with FALS were excluded. A whole- genome sequencing and parametric linkage analysis under the assumption of an autosomal-dominant mode of inheritance with incomplete penetrance revealed the mutation c.2780G>A (p. Arg927Gln) in ERBB4. An extensive mutational analysis revealed the same mutation in a Canadian individual with familial ALS and a de novo mutation, c.3823C>T (p. Arg1275Trp), in a Japanese simplex case. These amino acid substitutions involve amino acids highly conserved among species, are predicted as probably damaging, and are located within a tyrosine kinase domain (p. Arg927Gln) or a C-terminal domain (p. Arg1275Trp), both of which mediate essential functions of ErbB4 as a receptor tyrosine kinase. Functional analysis revealed that these mutations led to a reduced autophosphorylation of ErbB4 upon neuregulin-1 (NRG-1) stimulation. Clinical presentations of the individuals with mutations were characterized by the involvement of both upper and lower motor neurons, a lack of obvious cognitive dysfunction, and relatively slow progression. This study indicates that disruption of the neuregulin-ErbB4 pathway is involved in the pathogenesis of ALS and potentially paves the way for the development of innovative therapeutic strategies such using NRGs or their agonists to upregulate ErbB4 functions.
AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder characterized by the degeneration of motor neurons and typically results in death within 3-5 years from onset. Familial ALS (FALS) comprises 5%-10% of ALS cases, and the identification of genes associated with FALS is indispensable to elucidating the molecular pathogenesis.We identified a Japanese family affected by late-onset, autosomal-dominant ALS in which mutations in genes known to be associated with FALS were excluded. A whole- genome sequencing and parametric linkage analysis under the assumption of an autosomal-dominant mode of inheritance with incomplete penetrance revealed the mutation c.2780G>A (p. Arg927Gln) in ERBB4. An extensive mutational analysis revealed the same mutation in a Canadian individual with familial ALS and a de novo mutation, c.3823C>T (p. Arg1275Trp), in a Japanese simplex case. These amino acid substitutions involve amino acids highly conserved among species, are predicted as probably damaging, and are located within a tyrosine kinase domain (p. Arg927Gln) or a C-terminal domain (p. Arg1275Trp), both of which mediate essential functions of ErbB4 as a receptor tyrosine kinase. Functional analysis revealed that these mutations led to a reduced autophosphorylation of ErbB4 upon neuregulin-1 (NRG-1) stimulation. Clinical presentations of the individuals with mutations were characterized by the involvement of both upper and lower motor neurons, a lack of obvious cognitive dysfunction, and relatively slow progression. This study indicates that disruption of the neuregulin-ErbB4 pathway is involved in the pathogenesis of ALS and potentially paves the way for the development of innovative therapeutic strategies such using NRGs or their agonists to upregulate ErbB4 functions.
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U2 - 10.1016/j.ajhg.2013.09.008
DO - 10.1016/j.ajhg.2013.09.008
M3 - Article
C2 - 24119685
AN - SCOPUS:84890439549
SN - 0002-9297
VL - 93
SP - 900
EP - 905
JO - American journal of human genetics
JF - American journal of human genetics
IS - 5
ER -