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.

No abstract

No abstract

Митохондриальные заболевания-гетерогенная группа заболеваний, основной особенностью которых является дисфункция работы электротранспортной цепи митохондрий, приводящая к снижению митохондриального мембранного потенциала, росту продукции активных форм кислорода (АФК), снижению выработки клеточной энергии-аденизинтрифосфата (АТФ) и др. Это группа редких метаболических заболеваний, вместе с тем суммарная частота в популяции, по раз-личным данным, доходит до 1:5000 случаев. Клинически митохондриальные болезни могут проявляться нарушением работы различных органов и систем с преимущественным поражением тканей с высокой метаболической активностью (нервной и мышечной систем, печени) [1]. К одной из самых частых митохондриальных патологий относятся наследственные оптические нейропатии (НОН). Наиболее распространены наследственная оптическая нейропатия Лебера (НОНЛ),

Purpose. To assess the retinal ganglion cells function in patients with Leber's hereditary optic neuropathy (LHON) by registering the photopic negative response (PhNR) while the photopic electroretinography is performed. Material and methods. 14 patients with different LHON mutations and 9 healthy individuals were examined. A standard ophtalmological examination was performed, including visual fields, spectral optical coherence tomography, photopic electroretinography and PhNR tests. Results. Significant differences in the PhNR latency (68.4±4.01/64.28±5.37, p<0,01) and the PhNR amplitude (21.5±9.34/32.72±12.73, p<0,003) were revealed in patients with LHON and the control group. The study revealed significant differences between the PhNR latency (р<0.01) and the PhNR amplitude (р<0.008) in patients with visual acuity (VA) ≤ 0.1 and the control group, and between the PhNR amplitude in patients with VA≥0.13 and the control group (р<0.05). There were found significant correlations between the PhNR parameters and visual acuity, mean sensitivity, RNFL and GCC thickness. A strong positive correlation was found between the PhNR amplitude and the GCC thickness in patients with VA≥0.3. Conclusion. The PhNR parameters reflect the retinal ganglion cells function in patients with LHON and correlate with RNFL and GCC structural changes. Key words: Leber hereditary optic neuropathy, mitochondrial optical neuropathies, retinal ganglion cell, photopic negative response, PhNR.