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

Debby Hellebrekers 1 Tom Theunissen 2 Irenaeus de Coo 3 Hubert Smeets 2 Thuy-Linh Le 4 Louise Galmiche 5, 6 Jonathan Levy 7, 8 Pim Suwannarat 9 Debby M.E.I. Hellebrekers Khomgrit Morarach 10 Franck Boismoreau 11 Tom E.J. Theunissen Mathilde Lefebvre 12 Anna Pelet 4 Jelena Martinovic 13 Antoinette Gelot 14, 15 Fabien Guimiot 8, 16 Amanda Calleroz 17 Cyril Gitiaux 6 Marie Hully 18 Olivier Goulet 19 Christophe Chardot 20 Severine Drunat 16, 8 Yline Capri 16 Christine Bole-Feysot 4 Patrick Nitschké 21 Sandra Whalen 12 Linda Mouthon 22 Holly Babcock Robert Hofstra 23 Irenaeus F.M. de Coo Anne-Claude Tabet 16, 24 Thierry Molina 25, 26 Boris Keren 22 Alice Brooks 27 Hubert J.M. Smeets Ulrika Marklund 10 Christopher Gordon 4 Stanislas Lyonnet 4, 28 Jeanne Amiel 29, 28 Nadège Bondurand 29
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 (UMR 8197/1024)
12 Service de Médecine Fœtale [AP-HP Hôpital Armand-Trousseau]
13 AP-HP - Hôpital Antoine Béclère [Clamart]
14 INMED - INSERM U1249 - Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université]
15 AP-HP - Hôpital Armand Trousseau [AP-HP]
16 Département de génétique [Robert Debré]
17 Children's National Medical Center
18 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
19 Service de pédiatrie générale [CHU Necker]
20 Département des urgences pédiatriques [CHU Necker]
21 IMAGINE [Marne-la-Vallée]
LIGM - Laboratoire d'Informatique Gaspard-Monge
22 Service de génétique [CHU Pitié-Salpêtrière]
23 Erasmus MC - Erasmus University Medical Center [Rotterdam]
24 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
25 Département de Pathologie [CHU Necker]
26 ERL 8254 - Equipe Inserm U1163 - Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications
Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU) : ERL8254
27 Erasmus University Rotterdam
28 Fédération de Génétique
29 Imagine - Institut Pasteur U1163 - Morphogenèse du cœur - Heart morphogenesis
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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https://hal-amu.archives-ouvertes.fr/hal-03173467
Contributor : Christophe Pellegrino <>
Submitted on : Thursday, March 18, 2021 - 5:58:31 PM
Last modification on : Saturday, March 20, 2021 - 3:13:31 AM

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Debby Hellebrekers, Tom Theunissen, Irenaeus de Coo, Hubert 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, American Society for Clinical Investigation, 2021, 131 (6), ⟨10.1172/jci145837⟩. ⟨hal-03173467⟩

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