ERBB2 – Hirschsprung Disease

Hirschsprung disease (HSCR) is a congenital enteric nervous system disorder characterized by intestinal aganglionosis leading to severe gastrointestinal dysmotility. While RET is the major gene implicated in isolated HSCR, recent exome sequencing has identified biallelic ERBB2 variants in patients with HSCR and related phenotypes, implicating ERBB2 in enteric neuron development (PMID:33497358).

In a cohort of eight unrelated individuals from multiple families presenting with HSCR, chronic intestinal pseudo-obstruction (CIPO), peripheral neuropathy, and arthrogryposis, homozygous missense variants in ERBB2 were identified, consistent with autosomal recessive inheritance. No additional segregating affected relatives were reported in these families (PMID:33497358).

All reported ERBB2 variants in these patients were missense changes. The prototypical variant, c.2129C>T (p.Ala710Val), affects the kinase domain of ERBB2 and was observed in multiple probands, establishing a recurrent allele linked to HSCR phenotypes.

Functional studies in patient-derived fibroblasts and overexpression systems demonstrated decreased ERBB2 protein levels and altered receptor phosphorylation for the p.Ala710Val mutant. Mouse single-cell RNA sequencing and a conditional ErbB3-deficient model revealed disruption of Nrg1/ErbB signaling in enteric progenitors, concordant with human gut histopathology (PMID:33497358; PMID:33720042).

Common variant analyses in a Han Chinese case-control study did not detect significant associations between ERBB2 SNPs and HSCR risk, suggesting that rare biallelic mutations rather than common polymorphisms underlie the ERBB2-HSCR link (PMID:32418639).

Overall, genetic and experimental data provide moderate clinical validity for ERBB2 in HSCR. Screening for ERBB2 biallelic variants should be considered in patients with syndromic aganglionosis. Future mechanistic work may refine pathogenic pathways and inform targeted therapies.

Key Take-home: Autosomal recessive ERBB2 mutations (e.g., c.2129C>T (p.Ala710Val)) disrupt NRG1/ERBB signaling in enteric progenitors, contributing to Hirschsprung disease and related dysmotility disorders.

References

• The Journal of clinical investigation • 2021 • Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans. PMID:33497358
• The Journal of clinical investigation • 2021 • Hirschsprung disease and more: dysregulation of ERBB2 and ERBB3. PMID:33720042
• Journal of pediatric surgery • 2020 • Common variants of NRG1 and ITGB4 confer risk of Hirschsprung disease in Han Chinese population. PMID:32418639

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