期刊
NATURE GENETICS
卷 42, 期 12, 页码 1131-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.706
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资金
- MRC [G0500695] Funding Source: UKRI
- Medical Research Council [G0500695] Funding Source: researchfish
- Medical Research Council [G0500695] Funding Source: Medline
- Telethon [GGP07019] Funding Source: Medline
An isolated defect of respiratory chain complex I activity is a frequent biochemical abnormality in mitochondrial disorders. Despite intensive investigation in recent years, in most instances, the molecular basis underpinning complex I defects remains unknown. We report whole-exome sequencing of a single individual with severe, isolated complex I deficiency. This analysis, followed by filtering with a prioritization of mitochondrial proteins, led us to identify compound heterozygous mutations in ACAD9, which encodes a poorly understood member of the mitochondrial acyl-CoA dehydrogenase protein family. We demonstrated the pathogenic role of the ACAD9 variants by the correction of the complex I defect on expression of the wildtype ACAD9 protein in fibroblasts derived from affected individuals. ACAD9 screening of 120 additional complex I-defective index cases led us to identify two additional unrelated cases and a total of five pathogenic ACAD9 alleles.
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