Identification of IDH3G, encoding the gamma subunit of mitochondrial isocitrate dehydrogenase, as a novel candidate gene for X-linked retinitis pigmentosa.

Abstract

Purpose: Retinitis pigmentosa (RP) is a genetically heterogeneous group of retinal degenerative disorders characterized by the loss rod and cone photoreceptors, leading to visual impairment and blindness. To date, X-linked RP has been associated with variants in three genes (RPGR, RP2, OFD1), while genetic defects at three loci (RP6, RP24, RP34) are yet unidentified. The aim of this study was to identify a novel candidate gene underlying X-linked RP.

Methods: Participants were identified from cohorts of genetically unsolved male individuals affected by RP, who underwent genome sequencing, exome sequencing, or candidate gene screening via direct Sanger sequencing at three referral centers. Specifically, two probands were identified at the National Reference Centre for Rare Retinal Diseases REFERET (Paris, France), two at Massachusetts Eye and Ear Hospital (Boston, MA, USA), and one at the National Reference Centre for Inherited Sensory Diseases MAOLYA (Montpellier, France). The pathogenicity of the identified variants was assessed using bioinformatic predictions, protein expression analyses, and mitochondrial function assays.

Results: We identified four rare single nucleotide variants in IDH3G (HGNC:5386), located at the RP34 locus on the X chromosome, as well as a complete gene deletion, in five unrelated male individuals affected with nonsyndromic RP. The variants segregated with the phenotype in all available family members. In all cases, the disease severity was intermediate. None had high myopia. IDH3G encodes the γ subunit of mitochondrial isocitrate dehydrogenase (IDH3), an enzyme involved in the citric acid cycle, which is expressed in the inner segments of photoreceptors. Variants in IDH3A and IDH3B, encoding the other subunits of IDH3, have already been associated with nonsyndromic autosomal recessive RP. Bioinformatic predictions and functional assays support a pathogenic role for the variants identified in this study, possibly though partial loss of enzymatic activity and mitochondrial function.

Conclusions: Our findings suggest that variants in IDH3G are a novel cause of X-linked RP, possibly by impairing mitochondrial function and ultimately resulting in photoreceptor degeneration.