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, 12)
,
Fabien Guimiot
(8, 15)
,
Amanda Calleroz
(16)
,
Cyril Gitiaux
(6)
,
Marie Hully
(17)
,
Olivier Goulet
(18)
,
Christophe Chardot
(19)
,
Severine Drunat
(15, 8)
,
Yline Capri
(15)
,
Christine Bole-Feysot
(4)
,
Patrick Nitschké
(4)
,
Sandra Whalen
(12)
,
Linda Mouthon
(20)
,
Holly E Babcock
,
Robert Hofstra
(21)
,
Irenaeus F.M. de Coo
,
Anne-Claude Tabet
(15, 22)
,
Thierry J Molina
(23, 24)
,
Boris Keren
(20)
,
Alice Brooks
(25)
,
Hubert J.M. Smeets
(2)
,
Ulrika Marklund
(10)
,
Christopher T Gordon
(4)
,
Stanislas Lyonnet
(4, 26)
,
Jeanne Amiel
(4, 6)
,
Nadège Bondurand
(27)
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
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
- Function : Author
- PersonId : 768767
- ORCID : 0000-0002-2190-6843
- IdRef : 110494709
Holly E Babcock
- Function : Author
Irenaeus F.M. de Coo
- Function : Author
Boris Keren
- Function : Author
- PersonId : 764775
- ORCID : 0000-0001-6172-8247
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.