SORBS2 is a genetic factor contributing to cardiac malformation of 4q deletion syndrome patients

Fei Liang; Bo Wang; Juan Geng; Guoling You; Jingjing Fa; Min Zhang; Hunying Sun; Huiwen Chen; Qihua Fu; Xiaoqing Zhang; Zhen Zhang

doi:10.7554/eLife.67481

SORBS2 is a genetic factor contributing to cardiac malformation of 4q deletion syndrome patients

Elife. 2021 Jun 8:10:e67481. doi: 10.7554/eLife.67481.

Authors

Fei Liang^#^{1

2}, Bo Wang^#³, Juan Geng³, Guoling You³, Jingjing Fa³, Min Zhang², Hunying Sun⁴, Huiwen Chen⁵, Qihua Fu³, Xiaoqing Zhang³, Zhen Zhang²

Affiliations

¹ Neonatal Intensive Care Unit, Shanghai Pediatric Congenital Heart Disease Institute and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Shanghai Pediatric Congenital Heart Disease Institute and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics, Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Key Laboratory of Pediatric Hematology and Oncology Ministry of Health and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ Department of thoracic and cardiac surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

^# Contributed equally.

Abstract

Chromosome 4q deletion is one of the most frequently detected genomic imbalance events in congenital heart disease (CHD) patients. However, a portion of CHD-associated 4q deletions without known CHD genes suggests unknown CHD genes within these intervals. Here, we have shown that knockdown of SORBS2, a 4q interval gene, disrupted sarcomeric integrity of cardiomyocytes and caused reduced cardiomyocyte number in human embryonic stem cell differentiation model. Molecular analyses revealed decreased expression of second heart field (SHF) marker genes and impaired NOTCH and SHH signaling in SORBS2-knockdown cells. Exogenous SHH rescued SORBS2 knockdown-induced cardiomyocyte differentiation defects. Sorbs2^-/- mouse mutants had atrial septal hypoplasia/aplasia or double atrial septum (DAS) derived from impaired posterior SHF with a similar expression alteration. Rare SORBS2 variants were significantly enriched in a cohort of 300 CHD patients. Our findings indicate that SORBS2 is a regulator of SHF development and its variants contribute to CHD pathogenesis. The presence of DAS in Sorbs2^-/- hearts reveals the first molecular etiology of this rare anomaly linked to paradoxical thromboembolism.

Keywords: 4q deletion syndrome; Notch1; SORBS2; Shh; developmental biology; double atrial septum; human; mouse; second heart field.

Publication types

Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

Adaptor Proteins, Signal Transducing / genetics*
Adaptor Proteins, Signal Transducing / metabolism
Adolescent
Animals
Case-Control Studies
Cell Differentiation*
Child
Child, Preschool
Chromosome Deletion
Chromosome Disorders / diagnosis
Chromosome Disorders / genetics*
Chromosomes, Human, Pair 4 / genetics
Databases, Genetic
Female
Gene Expression Regulation, Developmental
Genetic Predisposition to Disease
HEK293 Cells
Heart Defects, Congenital / diagnosis
Heart Defects, Congenital / genetics*
Heart Defects, Congenital / metabolism
Hedgehog Proteins / genetics
Hedgehog Proteins / metabolism
Human Embryonic Stem Cells / metabolism*
Human Embryonic Stem Cells / pathology
Humans
Infant
Infant, Newborn
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
Myocytes, Cardiac / metabolism*
Myocytes, Cardiac / pathology
Phenotype
RNA-Binding Proteins / genetics*
RNA-Binding Proteins / metabolism
Receptors, Notch / genetics
Receptors, Notch / metabolism
Signal Transduction

Substances

Adaptor Proteins, Signal Transducing
Hedgehog Proteins
RNA-Binding Proteins
Receptors, Notch
SHH protein, human
SORBS2 protein, human
Sorbs2 protein, mouse

Supplementary concepts

Chromosome 4q- Syndrome

Associated data

SRA/PRJNA579193
GEO/GSE137090
GEO/GSE131181
GEO/GSE126128

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.