J Med Genet. 2023 Apr 3:jmg-2022-108888. doi: 10.1136/jmg-2022-108888. Online ahead of print.
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.