ArticleAmerican journal of human genetics2013
ERBB4 mutations that disrupt the neuregulin-ErbB4 pathway cause amyotrophic lateral sclerosis type 19.
Article in American journal of human genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 88 papers, 2 of them syntheses that pooled it.
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Who cites it
88 citing papers in PubMed, 2 syntheses or guidelines pooled it, 144 citations in OpenAlex.
- Gene-based association analysis of depression risk among European ancestry Parkinson's disease patients.Human genetics · 2026Pooled it
- Meta-analysis of Genetic Modifiers Reveals Candidate Dysregulated Pathways in Amyotrophic Lateral Sclerosis.Neuroscience · 2019Pooled it
- Targeting receptor tyrosine kinases: from molecular mechanisms to clinical therapeutics.Signal transduction and targeted therapy · 2026Review
- Review
- Maternal sleep deprivation reshapes offspring hippocampal development through a Trem2-centered microglial program revealed by single-nucleus and spatial transcriptomics.Molecular psychiatry · 2026Article
- Charting the human-specific properties of gene expression networks in the infant prefrontal cortex.Science advances · 2026Article
- Insight into Haploinsufficiency of the ERBB4 Gene: Expanding the Spectrum of Associated Phenotypes.Journal of autism and developmental disorders · 2026Article
- The retroelement-derived human protein PEG10 is a regulator of mRNA splicing in neurons.bioRxiv : the preprint server for biology · 2026Article
- Chronic Overexpression of Neuronal NRG1-III in Mice Causes Long-Term Detrimental Changes in Lower Motor Neurons, Neuromuscular Synapses and Motor Behaviour.International journal of molecular sciences · 2025Article
- Multiple Roles for Neuregulins and Their v-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog Receptors in Neurodegenerative Disease Pathogenesis and Therapy.The American journal of pathology · 2025Review
- Entering the era of precision medicine to treat amyotrophic lateral sclerosis.Molecular neurodegeneration · 2025Review
- Exploration of schizophrenia-related behavioral and molecular abnormalities in a mutant mouse model with a mutation in the TVV motif of the ErbB4 gene.Molecular brain · 2025Article
- Kv2/Kv6.4 Heteromeric Potassium Channels Are Expressed in Spinal Motoneurons and Localized at C-Bouton Synapses.The European journal of neuroscience · 2025Article
- Cross-tissue MiRNA profiling of extracellular vesicles and PBMCs from amyotrophic lateral sclerosis patients.Scientific reports · 2025Article
- Article
- Genetic analysis ofFrontiers in aging neuroscience · 2025Article
- An Effective DNA Methylation Biomarker Screening Mechanism for Amyotrophic Lateral Sclerosis (ALS) Based on Comorbidities and Gene Function Analysis.Bioengineering (Basel, Switzerland) · 2024Article
- Genetic background of walking ability and its relationship with leg defects, mortality, and performance traits in turkeys (Meleagris gallopavo).Poultry science · 2024Article
- Genetic variants affecting mitochondrial function provide further insights for kidney disease.BMC genomics · 2024Article
- Article
28 more citing papers are in PubMed but not listed here.
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Authors and funding
40 authors at 15 institutions in 5 countries.
Funding
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.
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