PUBLICATION

Identification and functional characterization of BICD2 as a candidate disease gene in an consanguineous family with dilated cardiomyopathy

Authors
Luo, K., Zheng, C., Luo, R., Cao, X., Sun, H., Ma, H., Huang, J., Yang, X., Wu, X., Li, X.
ID
ZDB-PUB-220908-2
Date
2022
Source
BMC Medical Genomics   15: 189 (Journal)
Registered Authors
Wu, Xiushan
Keywords
BICD2, Dilated cardiomyopathy, RNA-seq, Zebrafish model
MeSH Terms
  • Adult
  • Animals
  • Cardiomyopathy, Dilated*/pathology
  • Consanguinity
  • Exome
  • Humans
  • Microtubule-Associated Proteins
  • Pedigree
  • Zebrafish/genetics
PubMed
36068540 Full text @ BMC Med. Genomics
Abstract
Familial dilated cardiomyopathy (DCM) is a genetic cardiomyopathy that is associated with reduced left ventricle function or systolic function. Fifty-one DCM-causative genes have been reported, most of which are inherited in an autosomal dominant manner. However, recessive DCM-causative gene is rarely observed.
Whole-exome sequencing (WES) was performed in a consanguineous family with DCM to identify candidate variants. Sanger sequencing was utilized to confirm the variant. We then checked the DCM candidate gene in 210 sporadic DCM cases. We next explored BICD2 function in both embryonic and adult bicd2-knockout zebrafish models. In vivo cardiac function of bicd2-knockout fish was detected by echocardiography and RNA-seq.
We identified an autosomal recessive and evolutionarily conserved missense variant, NM_001003800.1:c.2429G > A, in BICD2, which segregated with the disease phenotype in a consanguineous family with DCM. Furthermore, we confirmed the presence of BICD2 variants in 3 sporadic cases. Knockout of bicd2 resulted in partial embryonic lethality in homozygotes, suggesting a vital role for bicd2 in embryogenesis. Heart dilation and decreased ejection fraction, cardiac output and stroke volume were observed in bicd2-knockout zebrafish, suggesting a phenotype similar to human DCM. Furthermore, RNA-seq confirmed a larger transcriptome shift in in bicd2 homozygotes than in heterozygotes. Gene set enrichment analysis of bicd2-deficient fish showed the enrichment of altered gene expression in cardiac pathways and mitochondrial energy metabolism.
Our study first shows that BICD2 is a novel candidate gene associated with familial DCM, and our findings will facilitate further insights into the molecular pathological mechanisms of DCM.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping