Abstract
Leber’s hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was the first to be genetically defined by a point mutation in mitochondrial DNA (mtDNA). A molecular diagnosis is achieved in up to 95% of cases, the vast majority of which are accounted for by 3 mutations within mitochondrial complex I subunit–encoding genes in the mtDNA (mtLHON). Here, we resolve the enigma of LHON in the absence of pathogenic mtDNA mutations. We describe biallelic mutations in a nuclear encoded gene, DNAJC30, in 33 unsolved patients from 29 families and establish an autosomal recessive mode of inheritance for LHON (arLHON), which to date has been a prime example of a maternally inherited disorder. Remarkably, all hallmarks of mtLHON were recapitulated, including incomplete penetrance, male predominance, and significant idebenone responsivity. Moreover, by tracking protein turnover in patient-derived cell lines and a DNAJC30-knockout cellular model, we measured reduced turnover of specific complex I N-module subunits and a resultant impairment of complex I function. These results demonstrate that DNAJC30 is a chaperone protein needed for the efficient exchange of complex I subunits exposed to reactive oxygen species and integral to a mitochondrial complex I repair mechanism, thereby providing the first example to our knowledge of a disease resulting from impaired exchange of assembled respiratory chain subunits.
Highlights
Leber’s hereditary optic neuropathy (LHON, OMIM:535000) was first noted by Von Graefe in 1858 [1] and was formally described as a clinical entity bearing his name by Leber in 1871 [2]
In those investigated by whole-exome sequencing (WES), no biallelic pathogenic variants or variants of uncertain significance (VUS) were detected in nuclear genes encoding complex I subunits or assembly factors (Supplemental Table 2)
We describe a recessive phenocopy of mtLHON due to mutations in the nuclear gene DNAJC30, where we observe incomplete penetrance and male predominance, phenomena seldom occurring in recessive disease
Summary
Leber’s hereditary optic neuropathy (LHON, OMIM:535000) was first noted by Von Graefe in 1858 [1] and was formally described as a clinical entity bearing his name by Leber in 1871 [2]. LHON results from a rapidly evolving degenerative process and is unique among the hereditary optic atrophies in its clinical course. It presents with subacute, simultaneous or sequential, bilateral painless loss of central vision due to selective degeneration of the retinal ganglion cells (RGCs) and their axons. Though noted in its earliest descriptions to be transmitted through the maternal line [7], the inheritance pattern of LHON was only confirmed over 100 years later by the discovery of the first point mutation in mitochondrial DNA (mtDNA) Other rare mtDNA mutations account for a further approximately 5% [11], inclusive of variants associated with MELAS Other rare mtDNA mutations account for a further approximately 5% [11], inclusive of variants associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, OMIM:540000; refs. 12, 13, 14) and Leigh syndrome (infantile subacute necrotizing encephalopathy, OMIM:256000; refs. 15, 16)
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