DNAJC30 biallelic mutations extend mitochondrial complex I–deficient phenotypes to include recessive Leber’s hereditary optic neuropathy
Janey L. Wiggs
Janey L. Wiggs
Published March 15, 2021
Citation Information: J Clin Invest. 2021;131(6):e147734. https://doi.org/10.1172/JCI147734.
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Commentary

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

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.

Authors

Janey L. Wiggs

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Figure 1

Organization of human mitochondrial respiratory chain complex I subunits.

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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).