Identification and Functional Characterization of Bicaudal-D2 As A Candidate Disease Gene in Autosomal Recessive Consanguineous Family with Dilated Cardiomyopathy

Abstract

Familial Dilated cardiomyopathy (DCM) is a genetic cardiomyopathy with reduced left ventricle function or systolic function. Fifty-one genes have been reported to be associated with familial DCM, most of which are inherited in an autosomal dominant manner, while those caused by a recessive manner are rarely observed. Here we identified an autosome recessive and evolutionarily conserved missense variant, c.2429G>A: p.Arg810His, in bicaudal D homolog 2 (BICD2), which was segregated with the disease phenotype in a consanguineous family with DCM. Furthermore, we confirmed the presence of BICD2 variants in 3 of 210 sporadic DCM cases, highlighting its candidate causative role. Interestingly, we discovered that BICD2 expressed higher in cardiomyocytes from DCM than that from control by reanalyzing published scRNA-seq dataset GSE95140, implicating its possible involvement in cardiac function. We next explored BICD2 function in zebrafish model at both embryonic and adult stages. Knockout of bicd2 resulted in partial embryonic lethality in homozygotes, suggesting a vital role for bicd2 in embryogenesis. We performed zebrafish echocardiography to detect indices of ventricular size at the adult zebrafish stage. Intriguingly, dilated hearts, decreased ejection fraction, cardiac output and stroke volume were observed, suggesting a phenotype similar to human DCM in bicd2-knockout homozygotes. Furthermore, RNA-seq confirmed the largest transcriptome shift in bicd2 homozygotes. Gene Set Enrichment Analysis(GSEA) of bicd2-deficient fish showed altered gene expression enriched in cardiac pathways and mitochondrial energy metabolism. In conclusion, we found for the first time that an autosomal recessive bicd2 variant is associated with familial and knockout of zebrafish bicd2 resulted in a phenotype similar to that of human DCM. Our findings provide further insight into the molecular pathological mechanism of DCM.