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Comment
. 2021 Mar 15;131(6):e147734.
doi: 10.1172/JCI147734.

DNAJC30 biallelic mutations extend mitochondrial complex I-deficient phenotypes to include recessive Leber's hereditary optic neuropathy

Janey L Wiggs
Comment

DNAJC30 biallelic mutations extend mitochondrial complex I-deficient phenotypes to include recessive Leber's hereditary optic neuropathy

Janey L Wiggs. J Clin Invest. .

Abstract

Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disease and in most cases is caused by mutations in mitochondrial DNA-encoded (mtDNA-encoded) respiratory complex I subunit ND1, ND4, or ND6. In this issue of the JCI, Stenton et al. describe biallelic mutations in a nuclear DNA-encoded gene, DNAJC30, establishing recessively inherited LHON (arLHON). Functional studies suggest that DNAJC30 is a protein chaperone required for exchange of damaged complex I subunits. Hallmark mtDNA LHON features were also found in arLHON, including incomplete penetrance, male predominance, and positive response to idebenone therapy. These results extend complex I-deficient phenotypes to include recessively inherited optic neuropathy, with important clinical implications for genetic counseling and therapeutic considerations.

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Conflict of interest statement

Conflict of interest: The author has received research support from Aerpio Pharmaceuticals.

Figures

Figure 1
Figure 1. Organization of human mitochondrial respiratory chain complex I subunits.
The 45 complex I (CI) subunits (shown as hexagons) are organized according to the three functional modules (N, electron accepting; Q, ubiquinone reducing; and P, proton pumping). Some gene mutations encode subunits that result in severe early-onset multisystem disease (orange), while other gene mutations encode subunits that cause LHON (green) or have not been associated with a human phenotype (gray). The four DNAJC30 interacting partners identified by Stenton et al. (18) also have a high turnover rate (outlined in red). Figure was modified with permission from Fassone and Rahman (8).
See this image and copyright information in PMC

Comment on

  • Impaired complex I repair causes recessive Leber's hereditary optic neuropathy.
    Stenton SL, Sheremet NL, Catarino CB, Andreeva NA, Assouline Z, Barboni P, Barel O, Berutti R, Bychkov I, 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 TD, Kunz WS, La Morgia C, Lamperti C, Ludwig C, Malacarne PF, Maresca A, Mayr JA, Meisterknecht J, Nevinitsyna TA, Palombo F, Pode-Shakked B, Shmelkova MS, Strom TM, Tagliavini F, Tzadok M, van der Ven AT, Vignal-Clermont C, Wagner M, Zakharova EY, Zhorzholadze NV, Rozet JM, Carelli V, Tsygankova PG, Klopstock T, Wittig I, Prokisch H. Stenton SL, et al. J Clin Invest. 2021 Mar 15;131(6):e138267. doi: 10.1172/JCI138267. J Clin Invest. 2021. PMID: 33465056 Free PMC article.

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