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.

中文翻译：

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辅酶 Q8B 是一种参与辅酶 Q10 生物合成的基因，其双等位基因变异导致非综合征性视网膜色素变性


视网膜色素变性 （RP） 是一种孟德尔疾病，其特征是由于视网膜细胞进行性变性而导致视力逐渐丧失。从遗传学上讲，它具有高度异质性，迄今为止已在 100 多个基因中鉴定出致病性变异。经过大规模测序筛选，我们确定了 5 个隐性和非综合征性 RP 个体 （4 个家庭），携带 COQ8B 的双等位基因 DNA 变化，COQ8B 是参与辅酶 Q10 生物合成的基因。具体来说，我们检测到了五种致病变异 （c.187C>T [p.Arg63Trp]、c.566G>A [p.Trp189Ter]、c.1156G>A [p.Asp386Asn]、c.1324G>A [p.Val442Met] 和 c.1560G>A [p.Trp520Ter]）的复合杂合子分类，所有这些都根据隐性遗传模式与疾病分离。通过靶标结合测定对来自这些基因型的重组蛋白进行基于细胞的分析显示，与野生型相比，在所有情况下，配体-蛋白质相互作用均显著减少。我们的结果表明，COQ8B 中的变异导致隐性非综合征性 RP，可能是通过损害辅酶 Q10 的生物合成，辅酶 Q10 是线粒体氧化磷酸化的关键成分。