PUBLICATION

Mutations in VWA8 cause autosomal-dominant retinitis pigmentosa via aberrant mitophagy activation

Authors
Kong, L., Chu, G., Ma, W., Liang, J., Liu, D., Liu, Q., Wei, X., Jia, S., Gu, H., He, Y., Luo, W., Cao, S., Zhou, X., He, R., Yuan, Z.
ID
ZDB-PUB-230404-63
Date
2023
Source
Journal of Medical Genetics   60(10): 939-950 (Journal)
Registered Authors
Keywords
genetic variation, genetics, mutation
MeSH Terms
  • Humans
  • Retinitis Pigmentosa*/diagnosis
  • Zebrafish*/genetics
  • Pedigree
  • Animals
  • Mutation/genetics
  • Mitophagy/genetics
(all 7)
PubMed
37012052 Full text @ J. Med. Genet.
Abstract
Background Although retinitis pigmentosa (RP) is the most common type of hereditary retinal dystrophy, approximately 25%-45% of cases remain without a molecular diagnosis. von Willebrand factor A domain containing 8 (VWA8) encodes a mitochondrial matrix-targeted protein; its molecular function and pathogenic mechanism in RP remain unexplained.
Methods Family members of patients with RP underwent ophthalmic examinations, and peripheral blood samples were collected for exome sequencing, ophthalmic targeted sequencing panel and Sanger sequencing. The importance of VWA8 in retinal development was demonstrated by a zebrafish knockdown model and cellular and molecular analysis.
Results This study recruited a Chinese family of 24 individuals with autosomal-dominant RP and conducted detailed ophthalmic examinations. Exome sequencing analysis of six patients revealed heterozygous variants in VWA8, namely, the missense variant c.3070G>A (p.Gly1024Arg) and nonsense c.4558C>T (p.Arg1520Ter). Furthermore, VWA8 expression was significantly decreased both at the mRNA and protein levels. The phenotypes of zebrafish with VWA8 knockdown are similar to those of clinical individuals harbouring VWA8 variants. Moreover, VWA8 defects led to severe mitochondrial damage, resulting in excessive mitophagy and the activation of apoptosis.
Conclusions VWA8 plays a significant role in retinal development and visual function. This finding may provide new insights into RP pathogenesis and potential genes for molecular diagnosis and targeted therapy.
Genes / Markers
Figures
No images available
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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Citation
Kong, L., Chu, G., Ma, W., Liang, J., Liu, D., Liu, Q., Wei, X., Jia, S., Gu, H., He, Y., Luo, W., Cao, S., Zhou, X., He, R., Yuan, Z. (2023) Mutations in VWA8 cause autosomal-dominant retinitis pigmentosa via aberrant mitophagy activation. Journal of Medical Genetics. 60(10):939-950.