Compound heterozygous mutation of the ASXL3 gene causes autosomal recessive congenital heart disease

AbstractTo explore mutations in the additional sex combs-like 3 (ASXL3) gene in two Chinese families with congenital heart disease (CHD). Whole-exome sequencing (WES) was used to reveal a novel compound heterozygous mutation in theASXL3 gene that was associated with CHD. Sanger sequencing of a further 122 CHD patients was used to determine an additional compound heterozygous mutation in theASXL3 gene. Cell apoptosis was examined by MTS assay and flow cytometry. The cardiac structure was identified via hematoxylin –eosin (HE), Masson’s trichrome, and ultrasound scanning. RNA sequencing was performed to identify a series of differentially expressed mRNAs. The mRNA and protein expressions were identified by quantitative real-time PCR and western blotting, respectively. A compound heterozygous mutation c.216 8C >  G (p.Pro723Arg) and c.5449C >  G (p.Pro1817Ala) in theASXL3 gene associated with CHD was identified. Overexpression of this compound heterozygous mutation in HL-1 cells resulted in increased apoptosis and reduced cell viability. Moreover, it affected cardiac structure and fibrosis in mice. There were 126 downregulated mRNAs and 117 upregulated mRNAs between theASXL3 compound heterozygous mutation c.2168C  >  G (p.Pro723Arg) and c.5449C >  G (p.Pro1817Ala) mice and wild-type mice.Ezh2,Slc6a4, andSocs3, which could interact withASXL3 through proteins, were all upregulated. Another compound heterozygous mutation c.3526C  >  T (p.Arg11...

Source: Human Genetics - July 20, 2020 Category: Genetics & Stem Cells Source Type: research