Related Experiment Video
Updated: Jul 10, 2025
Observing Mitotic Division and Dynamics in a Live Zebrafish Embryo
Published on: July 15, 2016
ERBB3 deficiency causes a multisystemic syndrome in human patient and zebrafish
Keqiang Liu1,2,3, Ru Chen1, Minzhong Zhang1
1Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
The Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene was first identified as a cause of lethal congenital contracture syndrome (OMIM 607598), while a recent study reported six additional patients carrying ERBB3 variants which exhibited distinct clinical features with evident intestinal dysmotility (OMIM 243180). The potential connection between these phenotypes remains unknown, and the ERBB3-related phenotype spectrum needs to be better characterized. Here, we described a patient presenting with a multisystemic syndrome including skip segment Hirschsprung disease, bilateral clubfoot deformity, and cardiac defect. Trio-whole exome sequencing revealed a novel compound heterozygous variant (c.1914-7C>G; c.2942_2945del) in the patient's ERBB3 gene. RT-PCR and in vitro minigene analysis demonstrated that variant c.1914-7C>G caused aberrant mRNA splicing. Both variants resulted in premature termination codon and complete loss of ERBB3 function. erbb3b knockdown in zebrafish simultaneously caused a reduction in enteric neurons in the distal intestine, craniofacial cartilage defects, and micrognathia, which phenotypically mimics ERBB3-related intestinal dysmotility and some features of lethal congenital contracture syndrome in human patients. These findings provide further patient and animal evidence supporting that ERBB3 deficiency causes a complex syndrome involving multiple systems with phenotypic variability among distinct individuals.
Insights
Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene variants cause a complex syndrome with varied symptoms, including intestinal dysmotility and congenital contractures. This study identifies new variants and uses zebrafish models to confirm ERBB3
Area of Science:
- Genetics
- Developmental Biology
- Molecular Biology
Background:
- The Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene is linked to lethal congenital contracture syndrome and distinct phenotypes with intestinal dysmotility.
- The full spectrum of ERBB3-related phenotypes and the connection between known conditions remain unclear.
Purpose of the Study:
- To characterize the ERBB3-related phenotype spectrum.
- To investigate the molecular mechanisms underlying ERBB3-associated disorders.
- To establish a link between ERBB3 variants and multisystemic congenital anomalies.
Main Methods:
- Trio-whole exome sequencing to identify genetic variants in a patient with a multisystemic syndrome.
- RT-PCR and in vitro minigene analysis to assess the impact of a specific ERBB3 variant on mRNA splicing.
- Zebrafish (erbb3b) knockdown model to investigate phenotypic consequences of ERBB3 deficiency.
Main Results:
- A patient presented with a novel compound heterozygous variant in the ERBB3 gene, causing skip segment Hirschsprung disease, bilateral clubfoot, and cardiac defects.
- The identified ERBB3 variants led to aberrant mRNA splicing, premature termination codons, and complete loss of ERBB3 function.
- Zebrafish erbb3b knockdown mimicked ERBB3-related intestinal dysmotility, craniofacial defects, and micrognathia, supporting ERBB3's role in these conditions.
Conclusions:
- ERBB3 deficiency causes a complex, multisystemic syndrome with significant phenotypic variability.
- The findings expand the known clinical spectrum associated with ERBB3 variants.
- This study provides crucial patient and animal model evidence for ERBB3's role in congenital anomalies.
