Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 93, Issue 3, Pages 471-481Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2013.07.017
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Funding
- Texas Norman Hackerman Advanced Research Program [[THECB] 02006]
- Cytometry and Cell Sorting Core at Baylor College of Medicine
- National Institutes of Health [AI036211, CA125123, RR024574]
- NHARP [0049-0041-2009]
- Medical Research Council (UK) Centenary Early Career Award
- HEFCE/DoH Clinical Senior Lecturer Award
- Wellcome Trust Strategic Award [096919/Z/11/Z]
- MRC Centre for Neuromuscular Diseases [G0601943]
- Lily Foundation
- UK NHS Specialist Commissioners
- Wellcome Trust [096919/Z/11/Z] Funding Source: Wellcome Trust
- MRC [MR/K000608/1, G0800674, G0601943] Funding Source: UKRI
- Medical Research Council [G0601943, MR/K000608/1] Funding Source: researchfish
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Nuclear genetic disorders causing mitochondrial DNA (mtDNA) depletion are clinically and genetically heterogeneous, and the molecular etiology remains undiagnosed in the majority of cases. Through whole-exome sequencing, we identified recessive nonsense and splicing mutations in FBXL4 segregating in three unrelated consanguineous kindreds in which affected children present with a fatal encephalopathy, lactic acidosis, and severe mtDNA depletion in muscle. We show that FBXL4 is an F-box protein that colocalizes with mitochondria and that loss-of-function and splice mutations in this protein result in a severe respiratory chain deficiency, loss of mitochondrial membrane potential, and a disturbance of the dynamic mitochondrial network and nucleoid distribution in fibroblasts from affected individuals. Expression of the wild-type FBXL4 transcript in cell lines from two subjects fully rescued the levels of mtDNA copy number, leading to a correction of the mitochondrial biochemical deficit. Together our data demonstrate that mutations in FBXL4 are disease causing and establish FBXL4 as a mitochondrial protein with a possible role in maintaining mtDNA integrity and stability.
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