期刊
CLINICAL GENETICS
卷 98, 期 2, 页码 155-165出版社
WILEY
DOI: 10.1111/cge.13773
关键词
complex I deficiency; CX9C motif; disulfide relay import pathway; mitochondrial disease; mitochondrial intermembrane space; OXPHOS
资金
- Japan Agency for Medical Research and Development [JP19ek0109273, JP19kk0205014, JP20ek0109468, JP20kk0305015]
- Japan Society for the Promotion of Science [JP19H03624]
- Ministry of Education, Culture, Sports, Science and Technology
- National Health and Medical Research Council [1107094, 1164459]
- National Health and Medical Research Council of Australia [1164459, 1107094] Funding Source: NHMRC
Mitochondrial complex I deficiency is caused by pathogenic variants in mitochondrial and nuclear genes associated with complex I structure and assembly. We report the case of a patient with & x3000;NDUFA8-related mitochondrial disease. The patient presented with developmental delay, microcephaly, and epilepsy. His fibroblasts showed apparent biochemical defects in mitochondrial complex I. Whole-exome sequencing revealed that the patient carried a homozygous variant in NDUFA8. His fibroblasts showed a reduction in the protein expression level of not only NDUFA8, but also the other complex I subunits, consistent with assembly defects. The enzyme activity of complex I and oxygen consumption rate were restored by reintroducing wild-typeNDUFA8 cDNA into patient fibroblasts. The functional properties of the variant in NDUFA8 were also investigated using NDUFA8 knockout cells expressing wild-type or mutated NDUFA8 cDNA. These experiments further supported the pathogenicity of the variant in complex I assembly. This is the first report describing that the loss of NDUFA8, which has not previously been associated with mitochondrial disease, causes severe defect in the assembly of mitochondrial complex I, leading to progressive neurological and developmental abnormalities.
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