Predisposition to atrioventricular septal defects may be caused by SOX7 variants that impair interaction with GATA4

• Published in: Molecular genetics and genomics : MGG Vol. 297; no. 3; pp. 671 - 687
• Main Authors: Li, Baolei, Li, Zhuoyan, Yang, Jianping, Hong, Nanchao, Jin, Lihui, Xu, Yuejuan, Fu, Qihua, Sun, Kun, Yu, Yu, Lu, Yanan, Chen, Sun
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-05-2022; Springer Nature B.V
• Subjects: Animal Genetics and Genomics; Animals; Biochemistry; Biomedical and Life Sciences; Chromatin; Defects; Endothelial cells; Etiology; GATA4 Transcription Factor - genetics; Gene expression; Genetic Predisposition to Disease; Genetics; Genomes; Genomics; Health care; Heart; Heart Septal Defects - genetics; Hospitals; Human Genetics; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Immunoprecipitation; Life Sciences; Mammals; Medicine; Microbial Genetics and Genomics; Morphogenesis; Mutation; Original Article; Pathogenicity; Patients; Plant Genetics and Genomics; Prenatal diagnosis; SOXF Transcription Factors - genetics; SOXF Transcription Factors - metabolism; Stem cells; Transcription factors; Transcription Factors - genetics; Umbilical vein; Atrioventricular septal defect; GATA4; SOX7; Interaction; Single nucleotide variant
• ISSN: 1617-4615; 1617-4623
• DOI: 10.1007/s00438-022-01859-5

Atrioventricular septal defects (AVSD) are a complicated subtype of congenital heart defects for which the genetic basis is poorly understood. Many studies have demonstrated that the transcription factor SOX7 plays a pivotal role in cardiovascular development. However, whether
SOX7
single nucleotide variants are involved in AVSD pathogenesis is unclear. To explore the potential pathogenic role of
SOX7
variants, we recruited a total of 100 sporadic non-syndromic AVSD Chinese Han patients and screened
SOX7
variants in the patient cohort by targeted sequencing. Functional assays were performed to evaluate pathogenicity of nonsynonymous variants of
SOX7
. We identified three rare SOX7 variants, c.40C > G, c.542G > A, and c.743C > T, in the patient cohort, all of which were found to be highly conserved in mammals. Compared to the wild type, these
SOX7
variants had increased mRNA expression and decreased protein expression. In developing hearts, SOX7 and GATA4 were highly expressed in the region of atrioventricular cushions. Moreover, SOX7 overexpression promoted the expression of GATA4 in human umbilical vein endothelial cells. A chromatin immunoprecipitation assay revealed that SOX7 could directly bind to the
GATA4
promoter and luciferase assays demonstrated that SOX7 activated the
GATA4
promoter. The SOX7 variants had impaired transcriptional activity relative to wild-type SOX7. Furthermore, the SOX7 variants altered the ability of GATA4 to regulate its target genes. In conclusion, our findings showed that deleterious
SOX7
variants potentially contribute to human AVSD by impairing its interaction with GATA4. This study provides novel insights into the etiology of AVSD and contributes new strategies to the prenatal diagnosis of AVSD.