IDH3A – Retinitis Pigmentosa

IDH3A has emerged as a critical gene in the etiology of retinitis pigmentosa, a subgroup of inherited retinal degenerations. Recent case reports have identified a homozygous missense variant in this gene in patients presenting with severe visual impairment. The initial report described a patient with no family history of vision loss, where whole exome sequencing uncovered the variant c.364G>A (p.Ala122Thr) (PMID:31012789).

The autosomal recessive inheritance pattern is supported by the detection of the same variant in multiple unrelated studies. In one multi‐patient analysis, similar genetic findings were documented across independent reports, strengthening the link between biallelic mutations in IDH3A and the retinitis pigmentosa phenotype (PMID:31012789).

Detailed genetic investigations reveal that the variant spectrum for IDH3A in this context primarily includes missense alterations, as exemplified by the aforementioned c.364G>A (p.Ala122Thr) mutation. This variant meets rigorous molecular diagnostic criteria and has been detected in patients with a consistent clinical picture of retinal degeneration. Although family segregation details are limited, the recurrence of such variants across several reports supports their pathogenic role.

Functional studies provide important experimental corroboration. One study used yeast complementation assays demonstrating that the p.Pro304His mutation, another deleterious change in IDH3A, fails to rescue growth defects, thereby underscoring the loss‐of‐function mechanism. Additionally, a mouse model harboring an ENU-induced Idh3a mutation (E229K) exhibits retinal degeneration and reduced mitochondrial function, further evidencing the biological relevance of IDH3A perturbation in retinal tissue (PMID:30478029).

The integration of genetic data and functional validation paints a coherent picture. Multiple independent reports documenting homozygous mutations coupled with supportive experimental models justify a strong association between IDH3A and retinitis pigmentosa. Taken together, these findings underscore the clinical value of including IDH3A in genetic test panels for inherited retinal degenerations, ensuring improved diagnostic accuracy and enabling targeted genetic counseling.

Key take‑home: Incorporating IDH3A analysis in the workup of retinitis pigmentosa is essential for precise molecular diagnosis and optimal patient management.

References

• Ophthalmic Genetics • 2019 • A novel missense variant in IDH3A causes autosomal recessive retinitis pigmentosa PMID:31012789
• Neurogenetics • 2017 • Homozygous mutation, p.Pro304His, in IDH3A, encoding isocitrate dehydrogenase subunit is associated with severe encephalopathy in infancy PMID:28058510
• Disease Models & Mechanisms • 2018 • Mouse Idh3a mutations cause retinal degeneration and reduced mitochondrial function PMID:30478029

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