ArticleThe Journal of clinical investigation2021
Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 46 citations in OpenAlex.
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- EMB is essential for enteric nervous system development mediated by PI3K signaling.Genome medicine · 2025Article
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- Association between prognostic nutritional index and all-cause mortality among intestinal obstruction patients in the intensive care unit: a retrospective study.Frontiers in nutrition · 2025Article
- Neuregulin 1 (NRG1) and its receptors in the enteric nervous system and other parts of the gastrointestinal wall.Histology and histopathology · 2024Review
- Cutting-edge regenerative therapy for Hirschsprung disease and its allied disorders.Surgery today · 2024Review
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- Peripheral Nervous System (PNS) Myelin Diseases.Cold Spring Harbor perspectives in biology · 2024Review
- BAP1 is required prenatally for differentiation and maintenance of postnatal murine enteric nervous system.The Journal of clinical investigation · 2024Article
- Prenatal diagnosis of fetal neurogenic megacystis associated with lethal congenital contractural syndrome 2.Case reports in perinatal medicine · 2024Article
- Hirschsprung disease.Nature reviews. Disease primers · 2023Review
- Comprehensive characterization of the genetic landscape of familial Hirschsprung's disease.World journal of pediatrics : WJP · 2023Review
- Irreversible tyrosine kinase inhibitors induce the endocytosis and downregulation of ErbB2.Biochemistry and biophysics reports · 2023Article
- Abnormally elevated expression of ACTA2 of circular smooth muscle leads to hyperactive contraction in aganglionic segments of HSCR.Pediatric surgery international · 2023Article
- Transcriptomics of Hirschsprung disease patient-derived enteric neural crest cells reveals a role for oxidative phosphorylation.Nature communications · 2023Article
- Pathogenicity of p.Phe147del in RET in familial Hirschsprung's disease.American journal of translational research · 2023Article
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Authors and funding
37 authors at 13 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hirschsprung disease (HSCR) is the most frequent developmental anomaly of the enteric nervous system, with an incidence of 1 in 5000 live births. Chronic intestinal pseudo-obstruction (CIPO) is less frequent and classified as neurogenic or myogenic. Isolated HSCR has an oligogenic inheritance with RET as the major disease-causing gene, while CIPO is genetically heterogeneous, caused by mutations in smooth muscle-specific genes. Here, we describe a series of patients with developmental disorders including gastrointestinal dysmotility, and investigate the underlying molecular bases. Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals variably associating HSCR, CIPO, peripheral neuropathy, and arthrogryposis. Thorough gut histology revealed aganglionosis, hypoganglionosis, and intestinal smooth muscle abnormalities. The cell type-specific ErbB3 and ErbB2 function was further analyzed in mouse single-cell RNA sequencing data and in a conditional ErbB3-deficient mouse model, revealing a primary role for ERBB3 in enteric progenitors. The consequences of the identified variants were evaluated using quantitative real-time PCR (RT-qPCR) on patient-derived fibroblasts or immunoblot assays on Neuro-2a cells overexpressing WT or mutant proteins, revealing either decreased expression or altered phosphorylation of the mutant receptors. Our results demonstrate that dysregulation of ERBB3 or ERBB2 leads to a broad spectrum of developmental anomalies, including intestinal dysmotility.
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