title: ERBB4 mutations that disrupt the neuregulin-ErbB4 pathway cause amyotrophic lateral sclerosis type 19.
abstract: 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.
authors.affiliation: Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Fukuda
authors.forename: Jun
authors.initials: J
authors.lastname: Yoshimura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Toyoda
authors.forename: Kari
authors.initials: K
authors.lastname: Kurppa
authors.forename: Hiroyoko
authors.initials: H
authors.lastname: Moritoyo
authors.forename: Veronique V
authors.initials: VV
authors.lastname: Belzil
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Dion
authors.forename: Koichiro
authors.initials: K
authors.lastname: Higasa
authors.forename: Koichiro
authors.initials: K
authors.lastname: Doi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishiura
authors.forename: Jun
authors.initials: J
authors.lastname: Mitsui
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Date
authors.forename: Budrul
authors.initials: B
authors.lastname: Ahsan
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsukawa
authors.forename: Yaeko
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Moritoyo
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ikoma
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Fumiharu
authors.initials: F
authors.lastname: Kimura
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
authors.forename: Masatoyo
authors.initials: M
authors.lastname: Nishizawa
authors.forename: Mari
authors.initials: M
authors.lastname: Yoshida
authors.forename: Naoki
authors.initials: N
authors.lastname: Atsuta
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Fifita
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Williams
authors.forename: Ian P
authors.initials: IP
authors.lastname: Blair
authors.forename: Garth A
authors.initials: GA
authors.lastname: Nicholson
authors.forename: Paloma
authors.initials: P
authors.lastname: Gonzalez-Perez
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nomoto
authors.forename: Klaus
authors.initials: K
authors.lastname: Elenius
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Asao
authors.initials: A
authors.lastname: Fujiyama
authors.forename: Shinichi
authors.initials: S
authors.lastname: Morishita
authors.forename: Jun
authors.initials: J
authors.lastname: Goto
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D044466:Asian People / Q000235:genetics; D002170:Canada; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D020880:Neuregulins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010766:Phosphorylation; D066247:Receptor, ErbB-4; D017422:Sequence Analysis, DNA; D015398:Signal Transduction
chemical_list: D020880:Neuregulins; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4