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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 4 Sandra Whalen 12 Linda Mouthon 21 Holly Babcock Robert Hofstra 22 Irenaeus F.M. de Coo Anne-Claude Tabet 16, 23 Thierry Molina 24, 25 Boris Keren 21 Alice Brooks 26 Hubert J.M. Smeets 2 Ulrika Marklund 10 Christopher Gordon 4 Stanislas Lyonnet 4, 27 Jeanne Amiel 4, 6 Nadège Bondurand 28
25 ERL 8254 - Equipe Inserm U1163 - Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications
Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU) : ERL8254
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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Submitted on : Thursday, March 18, 2021 - 5:58:31 PM
Last modification on : Thursday, May 12, 2022 - 9:04:07 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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