Biallelic mutations in COQ8B (ADCK4) lead to non-syndromic retinitis pigmentosa in multiple families

Abstract

Purpose : To investigate the genetic origin of recessive retinitis pigmentosa (RP) in 5 patients from 4 families who were negative for mutations in known disease genes associated with inherited retinal conditions.

Methods : Patients from Portugal and the UK were all ascertained by detailed ophthalmic examination. Whole exome sequencing (WES) or whole genome sequencing (WGS) was used to detect relevant genetic variants in all index patients. Sanger sequencing was used to assess segregation of the identified variants with disease. Mutant versions of COQ8B protein were obtained by transfecting of HEK293T cells with synthetic expression plasmids. Bioluminescence Resonance Energy Transfer Technology (NanoBRET) was used to assess the functional consequences of the variants detected in patients on COQ8B protein. Western blots were performed on extracts from human retina.

Results : WES/WGS analysis identified biallelic assortments of 5 causative variants in COQ8B (NP_079152.3: p.Arg63Trp, p.Trp520Ter, p.Val442Met, p.Asp386Asn, and p.Trp189Ter) in all index patients and one affected relative. All healthy family members were either monoallelic for such variants or had wild-type genotypes, confirming the recessive nature of the disease. NanoBRET tests showed that proteins bearing the variants detected in patients had significantly reduced ligand binding affinity, compared with the wild-type. Western blots showed the presence of COQ8B in the human retina.

Conclusions : This study shows that COQ8B is a new disease gene associated with non-syndromic RP. Our functional studies indicate that the mutations identified in patients likely impair COQ8B protein function, lead to defects in Coenzyme Q biosynthesis and, ultimately, to retinal disease.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.