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

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.

Graphical abstract

Figure 1

Structure of the families analyzed and their COQ8B genotypes Black arrows point to the proband of each family. A schematic structure of the gene (introns are not to scale) is also provided. NMD indicates the variant detected in family 4, M5, that likely triggers nonsense-mediated mRNA decay. The red area indicates the part of the coding sequence specifying the kinase domain of COQ8B.

Figure 2

Clinical findings of individuals with bi-allelic variants in COQ8B, as well as of a control subject Fundus photographs (a and b), fundus autofluorescence (FAF) (c and d), and optical coherence tomography (OCT) sections (e and f) are shown. For each individual, (a), (c), and (e) refer to the right eye, whereas (b), (d), and (f) refer to the left eye.

Figure 3

NanoBRET target engagement assay curves Data were obtained following the transfection of HEK293T cells with plasmids carrying the wild-type COQ8B cDNA sequence (black) or variants detected in family 1 (pink), families 2 and 3 (green), or family 4 (blue). All points represent the average values of at least 2 technical replicates (range 2–6) for each of 2 biological replicates. Statistical assessment was performed with respect to the wild-type sequence. Error bars indicate standard deviation. ^∗p value < 0.05; ^∗∗p value < 0.01; ^∗∗∗p value < 0.001, by 2-tailed t test. mBU, milli-BRET units.