期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 96, 期 2, 页码 309-317出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2014.12.023
关键词
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资金
- Fondazione Telethon [GGP11011]
- Italian Ministry of Health [GR2010-2316392]
- Fondazione CARIPLO [2011/0526]
- Mariani Foundation
- Italian Association of Mitochondrial Disease Patients and Families (Mitocon)
- European Research Council [FP7-322424]
- German Ministry of Education and Research through the E-Rare project GENOMIT [01GM1207, FWF I 920-B13, J41J11000420001]
- German Network for mitochondrial disorders (mitoNET) [01GM1113C]
- German Center for Heart Research by the German Research Foundation within the Munich Cluster for Systems Neurology [Z76010017300, Z56010015300, EXC-1010-SyNergy]
- UK Medical Research Council
- Spanish Instituto de Salud Carlos III [FIS-PI11-00078]
- Research Program of Innovative Cell Biology by Innovative Technology (Cell Innovation) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology
- Ministry of Health, Labour, and Welfare of Japan
- Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics
- Bank of Muscle Tissue, Peripheral Nerve, DNA, and Cell Culture of the Telethon Network of Genetic Biobanks [GTB12001J]
- MRC [MC_UP_1002/1] Funding Source: UKRI
- Austrian Science Fund (FWF) [I 920] Funding Source: researchfish
- Medical Research Council [MC_UP_1002/1] Funding Source: researchfish
Primary coenzyme Q10 (CoQ(10)) deficiencies are rare, clinically heterogeneous disorders caused by mutations in several genes encoding proteins involved in CoQ(10) biosynthesis. CoQ(10) is an essential component of the electron transport chain (ETC), where it shuttles electrons from complex I or II to complex III. By whole-exome sequencing, we identified five individuals carrying biallelic mutations in COQ4. The precise function of human COQ4 is not known, but it seems to play a structural role in stabilizing a multiheteromeric complex that contains most of the CoQ(10) biosynthetic enzymes. The clinical phenotypes of the five subjects varied widely, but four had a prenatal or perinatal onset with early fatal outcome. Two unrelated individuals presented with severe hypotonia, bradycardia, respiratory insufficiency, and heart failure; two sisters showed antenatal cerebellar hypoplasia, neonatal respiratory-distress syndrome, and epileptic encephalopathy. The fifth subject had an early-onset but slowly progressive clinical course dominated by neurological deterioration with hardly any involvement of other organs. All available specimens from affected subjects showed reduced amounts of CoQ(10) and often displayed a decrease in CoQ(10)-dependent ETC complex activities. The pathogenic role of all identified mutations was experimentally validated in a recombinant yeast model; oxidative growth, strongly impaired in strains lacking COQ4, was corrected by expression of human wild-type COQ4 cDNA but failed to be corrected by expression of COQ4 cDNAs with any of the mutations identified in affected subjects. COQ4 mutations are responsible for early-onset mitochondrial diseases with heterogeneous clinical presentations and associated with CoQ10 deficiency.
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