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

Debby M E I Hellebrekers (1) , Tom E J Theunissen (2) , Irenaeus F M de Coo (3) , Hubert J M 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 E Babcock , Robert Hofstra (22) , Irenaeus F.M. de Coo , Anne-Claude Tabet (16, 23) , Thierry J Molina (24, 25) , Boris Keren (21) , Alice Brooks (26) , Hubert J.M. Smeets (2) , Ulrika Marklund (10) , Christopher T Gordon (4) , Stanislas Lyonnet (4, 27) , Jeanne Amiel (4, 6) , Nadège Bondurand (28)

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 Service de Médecine Fœtale [CHU Trousseau]
13 AP-HP - Hôpital Antoine Béclère [Clamart]
14 INMED - INSERM U1249 - Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université]
15 CHU Trousseau [APHP]
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 Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière]
22 Erasmus MC - Erasmus University Medical Center [Rotterdam]
23 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
24 Département de Pathologie [CHU Necker]
25 ERL 8254 - Equipe Inserm U1163 - Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications
26 Erasmus University Rotterdam
27 Fédération de Génétique
28 Equipe Inserm U1163 - Embryology and genetics of human malformation

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.

Domains: Life Sciences [q-bio]

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⟩