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.

Neuregulin-1 promotes functional improvement by enhancing collateral sprouting in SOD1G93A ALS mice and after partial muscle denervation

“…This finding is in agreement with previous reports of loss-of-function ErbB4 mutations as causative of late-onset ALS (Takahashi et al, 2013).…”

“…It was recently reported that loss-of-function mutations on the Nrg1 receptor ErbB4 produce a form of late-onset, autosomal-dominant ALS in humans (Takahashi et al, 2013), opening a new field for searching novel therapeutic approaches. Thereby, the main goal of the present work was to determine the role of soluble Nrg1-I in ALS by assessing the effect of its overexpression at the NMJs in SOD1 G93A mice.…”

“…Loss-of-function mutations on Nrg1 receptor ErbB4 produce late-onset ALS in human patients (Takahashi et al, 2013). Because the manipulation of Nrg1 expression might represent a promising novel approach to treat ALS, the main goals of the present work were to investigate the contribution of the extracellular domain of Nrg1-I in ALS and to test the effect of its overexpression at the NMJs in SOD1 G93A ALS mice.…”

Clinical and genetic basis of familial amyotrophic lateral sclerosis

“…ALS19 (MIM #615515) represents a rare autosomal dominant form of late-onset slowly progressive familial ALS described in japanese and canadian families, resulting from heterozygous missense mutations in ERBB4 gene (V-ERB-B2 avian erythroblastic leucemia viral oncogene homolog 4; 2q34), coding the HER4 protein ligand for NDF/heregulin and neurregulin-ERBB4 pathways, involved in synaptic plasticity, cell proliferation and differentiation, glutamatergic hypofunction, and inhibition of NMDA currents and raise of AMPA currents 40 .…”

Activating ERBB4 mutations in non-small cell lung cancer

“…ERBB4 point mutations were introduced into pcDNA3.1.ERBB4JM-aCYT-2-HA and pBABE-puroERBB4JM-aCYT-2-HA by site-directed mutagenesis as previously described. 37 The pcDNA3.1.ERBB2 (ref. 13) construct was used to transiently overexpress ERBB2.…”