Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans - Aix-Marseille Université Access content directly
Journal Articles Journal of Clinical Investigation Year : 2021

Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans

1 MUMC - Maastricht University Medical Centre
2 Maastricht University [Maastricht]
3 Department of Toxicogenomics
4 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
5 TENS - The Enteric Nervous System in gut and brain disorders [U1235]
6 CHU Necker - Enfants Malades [AP-HP]
7 Hôpital Robert Debré Paris
8 NeuroDiderot (UMR_S_1141 / U1141) - Maladies neurodéveloppementales et neurovasculaires
9 MAMS Lab - Mid-Atlantic Mass Spectrometry Laboratory
10 Karolinska Institutet [Stockholm]
11 IBENS - Institut de biologie de l'ENS Paris
12 CHU Trousseau [APHP]
13 AP-HP - Hôpital Antoine Béclère [Clamart]
14 INMED - INSERM U1249 - Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université]
15 Département de génétique [Robert Debré]
16 Children's National Medical Center
17 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
18 Service de pédiatrie générale [CHU Necker]
19 Département des urgences pédiatriques [CHU Necker]
20 CHU Pitié-Salpêtrière [AP-HP]
21 Erasmus MC - Erasmus University Medical Center [Rotterdam]
22 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
23 Département de Pathologie [CHU Necker]
24 ERL 8254 - Mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques = Molecular mechanisms of hematological disorders and therapeutic implications
25 Erasmus University Rotterdam
26 Fédération de Génétique
27 Embryology and genetics of human malformation
Debby M.E.I. Hellebrekers
  • Function : Author
Tom E.J. Theunissen
  • Function : Author
Cyril Gitiaux
Sandra Whalen
Holly E Babcock
  • Function : Author
Irenaeus F.M. de Coo
  • Function : Author
Boris Keren


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.

Dates and versions

hal-03173467 , version 1 (18-03-2021)



Debby M E I Hellebrekers, Tom E J Theunissen, Irenaeus F M de Coo, Hubert J M Smeets, Thuy-Linh Le, et al.. Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans. Journal of Clinical Investigation, 2021, 131 (6), ⟨10.1172/jci145837⟩. ⟨hal-03173467⟩
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