Bi-allelic variants in COQ8B, a gene involved in the biosynthesis of coenzyme Q10, lead to non-syndromic retinitis pigmentosa
Retinitis pigmentosa (RP) is a Mendelian disease characterized by gradual loss of vision, due to the progressive degeneration of retinal cells. Genetically, it is highly heterogeneous, with pathogenic variants identified in more than 100 genes so far. Following a large-scale sequencing screening, we identified five individuals (four families) with recessive and non-syndromic RP, carrying as well bi-allelic DNA changes in COQ8B, a gene involved in the biosynthesis of coenzyme Q10. Specifically, we detected compound heterozygous assortments of five disease-causing variants (c.187C>T [p.Arg63Trp], c.566G>A [p.Trp189Ter], c.1156G>A [p.Asp386Asn], c.1324G>A [p.Val442Met], and c.1560G>A [p.Trp520Ter]), all segregating with disease according to a recessive pattern of inheritance. Cell-based analysis of recombinant proteins deriving from these genotypes, performed by target engagement assays, showed in all cases a significant decrease in ligand-protein interaction compared to the wild type. Our results indicate that variants in COQ8B lead to recessive non-syndromic RP, possibly by impairing the biosynthesis of coenzyme Q10, a key component of oxidative phosphorylation in the mitochondria.
Authors
- Carlo Rivolta (ORCID: https://orcid.org/0000-0002-0733-9950)
- Marc Folcher (ORCID: https://orcid.org/0000-0002-3544-0554)
- Ana Berta Sousa (ORCID: https://orcid.org/0000-0001-5889-2492)
- Siying Lin (ORCID: https://orcid.org/0000-0003-1122-8396)
- Cristina Santos (ORCID: https://orcid.org/0000-0002-7014-8014)
- Luísa Coutinho Santos (ORCID: https://orcid.org/0000-0002-6181-4505)
- Ana Belén Iglesias-Romero (ORCID: https://orcid.org/0000-0003-0044-179X)
- Karolina Kamińska (ORCID: https://orcid.org/0000-0002-4720-5527)
- Joaquim Calado (ORCID: https://orcid.org/0000-0002-1194-3392)
- Alexandre Moulin
- Gavin Arno
- Mathieu Quinodoz (ORCID: https://orcid.org/0000-0002-9841-4433)
- Andrew R. Webster (ORCID: https://orcid.org/0000-0001-6915-9560)
Institutions
- Moorfields Eye Hospital NHS Foundation Trust (GB)
- National Institute for Health and Care Research (GB)
- Nova Medical (United States) (US)
- Centro Hospitalar Lisboa Norte (PT)
- Fondation Asile des Aveugles (CH)
- Department of Biomedicine Basel (CH)
- Institute of Molecular and Clinical Ophthalmology Basel (CH)
- University College London (GB)
- Universidade Nova de Lisboa (PT)
- University of Lausanne (CH)
Publication Details
- Journal
- The American Journal of Human Genetics
- Published
- 2024-09-02
- DOI
- https://doi.org/10.1016/j.ajhg.2024.08.005
- Citations
- 3
- Primary Topic
- Coenzyme Q10 studies and effects
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- National Science Foundation
- Wellcome Trust
- Cancer Research UK
- National Institute for Health and Care Research
- Department of Health and Social Care
- Fight for Sight UK
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Moorfields Eye Hospital NHS Foundation Trust
- Moorfields Eye Charity
- Medical Research Council