Research Centre for Medical Genetics
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Identification of a new gene DNAJC30, with mutations leading to Leber’s hereditary optic neuropathy

Leber’s hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease in adults. The onset average age is 28 years. It mainly affects men (sex ratio M:W is 8:1). The disease manifests itself when patients begin to lose central vision in both eyes.

Leber’s hereditary optic neuropathy (LHON) is a rare, orphan disease with an incidence of about 1: 30,000 people. According to ophthalmologists, about 20% of patients with a clinical picture of LHON remained without molecular confirmation of the diagnosis; they could not detect a mutation in the gene that usually leads to the disease. This prompted an international study to search for new LHON genes.

The study began in 2018 at the Mitochondrial Genomics Laboratory of the Helmholtz Centre Neurogenomics Institute in Munich and Dr. Holger Prokisch headed it. The international team included biochemists, geneticists and ophthalmologists from 34 institutes. Specialists from the Eye Diseases Research Institute (head of the group - N.L. Sheremet) performed all ophthalmological examinations. The FSBI RCMG Hereditary Metabolic Diseases Laboratory (Laboratory head - E.Yu. Zakharova) performed genotyping of Russian patients, verified mutation inheritance, and analyzed its incidence in the population.

The study described 33 patients; 16 of them were identified in Russia; patients were also identified in Romania, Germany, Italy, and Ukraine. Patients with an unconfirmed diagnosis underwent exome sequencing - all sections of genes encoding proteins. As a result, they found changes in a previously undescribed DNAJC30gene, which function has not been studied.

The experiments showed that the DNAJC30 protein was a chaperone of the mitochondrial respiratory chain. Mutations in the DNAJC30 gene cause nonfunctional proteins to accumulate in the mitochondria and disrupt mitochondrial respiratory chain of cells, leading to a clinical disease pattern.

Mutations in the DNAJC30 gene are common to the Eastern European populations and are inherited by autosomal recessive type, i.e. the patients’ parents are healthy carriers of the mutation, while the patient who received one damaged copy of the gene from each of them becomes ill. It is interesting that patients with the DNAJC30 gene mutation are more likely to have the phenomenon of visual recovery.

Stenton SL, Sheremet NL, Catarino CB, Andreeva N, Assouline Z, Barboni P, Barel O, Berutti R, Bychkov IO, Caporali L, Capristo M, Carbonelli M, Cascavilla ML, Charbel Issa P, Freisinger P, Gerber S, Ghezzi D, Graf E, Heidler J, Hempel M, Heon E, Itkis YS, Javasky E, Kaplan J, Kopajtich R, Kornblum C, Kovacs-Nagy R, Krylova T, Kunz WS, La Morgia C, Lamperti C, Ludwig C, Malacarne PF, Maresca A, Mayr JA, Meisterknecht J, Nevinitsyna T, Palombo F, Pode-Shakked B, Shmelkova MS, Strom TM, Tagliavini F, Tzadok M, van der Ven AT, Vignal-Clermont C, Wagner M, Zakharova E, Zhorzholadze N, Rozet JM, Carelli V, Tsygankova P, Klopstock T, Wittig I, Prokisch H. Impaired complex I repair causes recessive Leber's hereditary optic neuropathy. J Clin Invest. 2021 Jan 19:138267. doi: 10.1172/JCI138267. Epub ahead of print. PMID: 33465056.