ERBB4 was first reported in relation to autosomal dominant amyotrophic lateral sclerosis 19 (meaning amyotrophic lateral sclerosis caused by variants in the ERBB4 gene rather than a distinct ALS phenotype) in 2013 (Takahashi et al., PMID:24119685). Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease involving death or loss of function of upper and lower motor neurons. ERBB4 is a membrane-bound receptor tyrosine kinase which binds ligands such as neuregulin, dimerises, usually with ErbB2 or ErbB3, and auto-phosphorylates on activation. At least 19 unique ERBB4 variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data.
2.9 points have been given for variants in this gene which have been reported in at least 7 publications (PMIDs: 24119685; 32065797; 32166880; 33414559; 31788332; 31432357; 28889094). The seminal paper (Takahashi et al., 2013 PMID:24119685) identified ERBB4 as a candidate gene in a family of 3 affected siblings, based on an assumption of reduced penetrance. A de novo variant in ERBB4 in a person with sporadic ALS was identified as part of this study. Other publications consist of a case study of an individual with ALS-FTD, and genetic epidemiology studies involving genotyping people enrolled in specialist ALS clinics and screening for variants in known or implicated ALS genes. The mechanism for disease is unknown. This gene-disease association is supported by an immunohistochemistry study (PMID: 31124187) investigating ErbB4 expression in the central nervous system of people with sporadic ALS compared to non-neuro disease controls and neuro disease controls. The study showed there was reduced ErbB4 in motor neurons correlating with severity of motor neuron loss, that the subcellular localization of ErbB4 was altered in people with sporadic ALS – ErbB4 was found in the nucleolus, in spheroids (previously associated with ALS pathogenicity) and in glial cells. There was a negative correlation between pathogenic subcellular localization of TDP-43 and presence of ErbB4 in motor neurons. ERBB4 mouse knock-out models produce an altered neuronal phenotype, but not an ALS phenotype (PMIDs: 14555954; 12824469; 15543145; 15976301).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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