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Genotype-phenotype correlations
Original research
Mutations in VWA8 cause autosomal-dominant retinitis pigmentosa via aberrant mitophagy activation
  1. Linghui Kong1,
  2. Guoming Chu2,
  3. Wei Ma1,
  4. Jiajian Liang3,
  5. Dan Liu1,
  6. Qiushi Liu4,
  7. Xiaowei Wei1,
  8. Shanshan Jia1,
  9. Hui Gu1,
  10. Yiwen He1,
  11. Wenting Luo1,
  12. Songying Cao1,
  13. Xiaomeng Zhou5,
  14. Rong He2,
  15. Zhengwei Yuan1
  1. 1 Key Laboratory of Health Ministry for Congenital Malformation, Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
  2. 2 Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
  3. 3 Department of Orthopedic Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
  4. 4 Department of Ophthalmology, Fourth People's Hospital of Shenyang, Shenyang, Liaoning, China
  5. 5 MyGenostics Inc, Beijing, China
  1. Correspondence to Dr Zhengwei Yuan, Key Laboratory of Health Ministry for Congenital Malformation, Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China; yuanzw{at}hotmail.com; Dr Rong He; her{at}sj-hospital.org

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.

  • genetic variation
  • mutation
  • genetics

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/jmg-2022-108888

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

    • LK and GC contributed equally.

    • Contributors ZY conceived the project, designed the experiments and supervised the study. ZY is responsible for all contents as guarantor. RH revised the manuscript. LK designed and performed the experiments, analysed the data, and drafted the manuscript and figures. GC collected information on retinitis pigmentosa family. WM and JL assisted in the animal model preparation and sample collection. XW, HG, DL, WL, SC, SJ, YH and QL assisted in the preparation of the manuscript. XZ assisted in exome sequencing data analysis. All authors read and approved the final manuscript.

    • Funding This work was supported by the National Key Research and Development Program (2021YFC2701104 and 2021YFC2701003), the National Natural Science Foundation of China (grant numbers 82171649, 81871219 and 82271730) and LiaoNing Revitalization Talents Program (XLYC1902099)

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.