IDH3G – Retinitis Pigmentosa

IDH3G encodes the γ subunit of mitochondrial isocitrate dehydrogenase and has been implicated as a novel candidate gene for X-linked retinitis pigmentosa. In a cohort of 5 unrelated male individuals affected with nonsyndromic RP (PMID:40119724), rare IDH3G variants were identified at the RP34 locus.

The inheritance is X-linked, consistent with exclusively male probands and maternal carrier transmission. Variants co-segregated with disease in all available family members across 5 pedigrees, confirming X-linked segregation.

Sequencing revealed 4 rare single-nucleotide variants and a complete gene deletion in IDH3G (PMID:40119724). No recurrent or founder alleles were observed, and all probands exhibited intermediate disease severity without high myopia.

Functional studies, including bioinformatic predictions, reduced γ subunit expression in photoreceptor inner segments, and mitochondrial assays, demonstrated partial loss of enzymatic activity consistent with a loss-of-function mechanism (PMID:40119724).

No conflicting evidence has been reported to date. These findings extend prior associations of IDH3A and IDH3B with autosomal recessive RP to an X-linked form involving IDH3G.

In summary, IDH3G variants are strongly supported as a cause of X-linked retinitis pigmentosa, with moderate genetic and functional evidence. Screening of IDH3G should be considered in unsolved X-linked RP cases to improve diagnostic yield.

References

• Genetics in Medicine • 2025 • Identification of IDH3G, encoding the gamma subunit of mitochondrial isocitrate dehydrogenase, as a novel candidate gene for X-linked retinitis pigmentosa. PMID:40119724

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