ERBB4 – ERBB4-related Amyotrophic Lateral Sclerosis (ALS-19)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by upper and lower motor neuron loss. Familial ALS accounts for 5–10% of cases, with autosomal-dominant inheritance in many pedigrees. ERBB4 (HGNC:3432) mutations disrupting the neuregulin-ErbB4 signaling pathway have been implicated in ALS type 19, providing a novel genetic etiology for both familial and sporadic presentations (PMID:24119685).

Genetic studies identified the ERBB4 missense variant c.2780G>A (p.Arg927Gln) segregating with disease in a Japanese pedigree under an autosomal-dominant model and confirmed this variant in an unrelated Canadian familial ALS case; a de novo ERBB4 c.3823C>T (p.Arg1275Trp) was also described in a simplex Japanese ALS patient (PMID:24119685). Subsequent screening in larger cohorts revealed additional rare ERBB4 missense variants, including c.308G>A (p.Arg103His) in 1/154 Indian patients and c.965T>A (p.Met322Lys) in 1/45 Chinese familial cases, and a burden study of 448 Chinese ALS patients reported three likely pathogenic ERBB4 variants (0.67%) absent from controls (PMID:35481267).

All reported ERBB4 variants in ALS are heterozygous missense changes located within the tyrosine kinase or C-terminal domains. No loss-of-function or structural variants have been reported to date. There is no evidence for founder alleles, and carrier frequency in ALS cohorts remains below 1%. Variants are absent or extremely rare in population databases, consistent with a dominant negative or haploinsufficiency mechanism.

Functional assays demonstrate that p.Arg927Gln and p.Arg1275Trp mutants show markedly reduced autophosphorylation upon neuregulin-1 stimulation in transfected cells, indicating impaired receptor activation (PMID:24119685). A novel variant, p.Asn706Asp, similarly exhibits decreased phosphorylation in NSC-34 motor neuron–like cells, confirming a loss-of-function effect on ErbB4 signaling (PMID:38278691). These data converge on disrupted neuregulin-ErbB4 pathway function as a key pathogenic mechanism.

Conflicting evidence arises from a genetic burden analysis in a Chinese ALS cohort that found no overall enrichment of damaging ERBB4 variants, suggesting variant-specific pathogenicity rather than a general susceptibility role for ERBB4 (PMID:35481267). Careful interpretation and variant classification are therefore required in genetic testing.

Together, multiple independent probands with segregating ERBB4 missense variants and concordant functional impairment support a Moderate ClinGen clinical validity classification. The mechanism involves haploinsufficiency or dominant-negative disruption of ErbB4 autophosphorylation. Key take-home: ERBB4 variant screening in familial or early-onset ALS can refine diagnosis and guide exploration of neuregulin-based therapeutic approaches.

References

• American journal of human genetics • 2013 • ERBB4 mutations that disrupt the neuregulin-ErbB4 pathway cause amyotrophic lateral sclerosis type 19. PMID:24119685
• Molecular genetics & genomic medicine • 2022 • Quadruple genetic variants in a sporadic ALS patient. PMID:35426263
• Journal of the neurological sciences • 2024 • Identification and characterization of novel ERBB4 variant associated with sporadic amyotrophic lateral sclerosis (ALS). PMID:38278691

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