Bi-allelic variants in COQ8B, a gene involved in the biosynthesis of coenzyme Q10, lead to non-syndromic retinitis pigmentosa

Ana Belén Iglesias-Romero; Karolina Kaminska; Mathieu Quinodoz; Marc Folcher; Siying Lin; Gavin Arno; Joaquim Calado; Andrew R Webster; Alexandre Moulin; Ana Berta Sousa; Luisa Coutinho-Santos; Cristina Santos; Carlo Rivolta

doi:10.1016/j.ajhg.2024.08.005

Bi-allelic variants in COQ8B, a gene involved in the biosynthesis of coenzyme Q10, lead to non-syndromic retinitis pigmentosa

Am J Hum Genet. 2024 Oct 3;111(10):2299-2306. doi: 10.1016/j.ajhg.2024.08.005. Epub 2024 Sep 2.

Authors

Affiliations

¹ Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland; Department of Ophthalmology, Universität Basel, 4031 Basel, Switzerland.
² Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland; Department of Ophthalmology, Universität Basel, 4031 Basel, Switzerland; Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK.
³ National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital and the Institute of Ophthalmology, London, UK; Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
⁴ National Institute of Health Research Biomedical Research Centre at Moorfields Eye Hospital and the Institute of Ophthalmology, London, UK; Institute of Ophthalmology, University College London, London EC1V 9EL, UK; Greenwood Genetic Center, Greenwood, SC 29646, USA.
⁵ ToxOmics, NOVA Medical School, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal.
⁶ Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, 1004 Lausanne, Switzerland.
⁷ Department of Medical Genetics, Centro Hospitalar Universitario Lisboa Norte EPE, 1649-028 Lisboa, Portugal; Laboratory of Basic Immunology, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal.
⁸ Instituto de Oftalmologia Dr. Gama Pinto, 1150-255 Lisboa, Portugal.
⁹ Instituto de Oftalmologia Dr. Gama Pinto, 1150-255 Lisboa, Portugal; iNOVA4Health, Universidade NOVA de Lisboa NOVA Medical School, 1150-082 Lisboa, Portugal.
¹⁰ Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland; Department of Ophthalmology, Universität Basel, 4031 Basel, Switzerland; Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK. Electronic address: [email protected].

Abstract

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.

Keywords: COQ8B; Mendelian diseases; coenzyme Q; inherited retinal diseases; retinitis pigmentosa.

MeSH terms

Adult
Alleles*
Female
Genes, Recessive
Heterozygote
Humans
Male
Middle Aged
Mutation
Pedigree*
Retinitis Pigmentosa* / genetics
Ubiquinone* / analogs & derivatives
Ubiquinone* / biosynthesis
Ubiquinone* / genetics

Substances

coenzyme Q10
Ubiquinone
COQ8B protein, human