DNAJC30 – Leber Hereditary Optic Neuropathy

DNAJC30 is a nuclear gene implicated in an autosomal recessive form of Leber hereditary optic neuropathy (LHON), a disorder characterized by painless, bilateral visual loss. Recent studies have consistently identified pathogenic variants in DNAJC30 that recapitulate the clinical spectrum of LHON, offering a valuable molecular diagnosis in cases negative for common mitochondrial mutations (PMID:38715355).

Multiple independent case reports and cohort studies have reported the recurrent identification of the founder variant c.152A>G (p.Tyr51Cys) in patients from Eastern Europe. This specific variant has been found in homozygous form in affected individuals and is supported by segregation data in families, validating its role in disease etiology (PMID:37579815).

Genetic evidence from these studies encompasses extensive case series where more than 50 probands overall present with the c.152A>G (p.Tyr51Cys) variant, along with additional rare alleles in DNAJC30. The autosomal recessive pattern is further highlighted by its occurrence in siblings and other affected relatives, reinforcing the gene–disease link (PMID:38139324).

Segregation analysis across multiple families has identified additional affected relatives carrying the variant, strengthening the observation of co‐segregation with the disease phenotype. These observations are consistent with a model of founder effect and pathogenicity, corroborated by detailed familial studies (PMID:38757769).

Functional assessments have demonstrated that mutations in DNAJC30, including the recurrent c.152A>G (p.Tyr51Cys), impair the repair mechanism of mitochondrial complex I. Cellular and knockout models show defective turnover of subunits in the complex, which mirrors the biochemical dysfunction observed in LHON patients and provides mechanistic insight into the disease process (PMID:33465056).

In conclusion, the integration of robust genetic data with supportive functional evidence establishes DNAJC30 as a critical gene in the pathogenesis of autosomal recessive LHON. This association not only enhances diagnostic precision but also informs therapeutic strategies, making DNAJC30 sequencing an essential component in the workup of LHON, particularly in patients of Eastern European descent.

References

• European Journal of Medical Genetics • 2023 • Autosomal recessive Leber's hereditary optic neuropathy caused by a homozygous variant in DNAJC30 gene PMID:37579815
• The Journal of Clinical Investigation • 2021 • Impaired complex I repair causes recessive Leber's hereditary optic neuropathy PMID:33465056
• European Journal of Ophthalmology • 2024 • Autosomal recessive leber hereditary optic neuropathy in a choroideremia carrier. A case report. PMID:38715355
• Journal of Medical Genetics • 2022 • DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy PMID:35091433

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