<i>SORBS2</i> is a genetic factor contributing to cardiac malformation of 4q deletion syndrome patients.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34099102.
- Also identified by DOI 10.7554/eLife.67481 and PMC identifier 8186900.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 <i>SORBS2</i>, 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 <i>SORBS2-</i>knockdown cells. Exogenous SHH rescued <i>SORBS2</i> knockdown-induced cardiomyocyte differentiation defects. <i>Sorbs2<sup>-/-</sup></i> mouse mutants had atrial septal hypoplasia/aplasia or double atrial septum (DAS) derived from impaired posterior SHF with a similar expression alteration. Rare <i>SORBS2</i> variants were significantly enriched in a cohort of 300 CHD patients. Our findings indicate that <i>SORBS2</i> is a regulator of SHF development and its variants contribute to CHD pathogenesis. The presence of DAS in <i>Sorbs2<sup>-/-</sup></i> hearts reveals the first molecular etiology of this rare anomaly linked to paradoxical thromboembolism.
Medical subject headings
- Adaptor Proteins, Signal Transducing
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism
- Adolescent
- Animals
- Case-Control Studies
- Cell Differentiation
- Child
- Child, Preschool
- Chromosome Deletion
- Chromosome Disorders
- Chromosome Disorders/diagnosis
- Chromosome Disorders/genetics
- Chromosomes, Human, Pair 4
- Chromosomes, Human, Pair 4/genetics
- Databases, Genetic
- Female
- Gene Expression Regulation, Developmental
- Genetic Predisposition to Disease
- HEK293 Cells
- Heart Defects, Congenital
- Heart Defects, Congenital/diagnosis
- Heart Defects, Congenital/genetics
- Heart Defects, Congenital/metabolism
- Hedgehog Proteins
- Hedgehog Proteins/genetics
- Hedgehog Proteins/metabolism
- Human Embryonic Stem Cells
- Human Embryonic Stem Cells/metabolism
- Human Embryonic Stem Cells/pathology
- Humans
- Infant
- Infant, Newborn
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Mutation
- Myocytes, Cardiac
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Phenotype
- RNA-Binding Proteins
- RNA-Binding Proteins/genetics
- RNA-Binding Proteins/metabolism
- Receptors, Notch
- Receptors, Notch/genetics
- Receptors, Notch/metabolism
- Signal Transduction
- Mice