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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance
American Journal of Human Genetics, Volume 93, No. 3, Year 2013
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Description
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. © 2013 The Authors.
Authors & Co-Authors
Bonnen, Penelope E.
United States, Houston
Baylor College of Medicine
Yarham, John W.
United Kingdom, Newcastle
Wellcome Trust Centre for Mitochondrial Research
Besse, Arnaud
United States, Houston
Baylor College of Medicine
Wu, Ping
United States, Houston
Baylor College of Medicine
Faqeih, Eissa Ali
Saudi Arabia, Riyadh
Children's Hospital
Al-Asmari, Ali Mohammad
Saudi Arabia, Riyadh
Children's Hospital
Saleh, Mohammed Ali M.
Saudi Arabia, Riyadh
Children's Hospital
Eyaid, Wafaa M.
Saudi Arabia, Riyadh
King Abdulaziz Medical City - Riyadh
Hadeel, Alrukban
Saudi Arabia, Riyadh
King Abdulaziz Medical City - Riyadh
He, Langping
United Kingdom, Newcastle
Wellcome Trust Centre for Mitochondrial Research
Smith, Frances J.D.
United Kingdom, London
Guy's Hospital
Yau, Shu
United Kingdom, London
Guy's Hospital
Simcox, Eve Michelle
United Kingdom, Newcastle
Wellcome Trust Centre for Mitochondrial Research
Miwa, Satomi
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
Donti, Taraka R.
United States, Houston
Baylor College of Medicine
Abu-Amero, Khaled Khader
Saudi Arabia, Riyadh
College of Medicine
Wong, Leejun C.
United States, Houston
Baylor College of Medicine
Craigen, William James
United States, Houston
Baylor College of Medicine
Graham, Brett H.
United States, Houston
Baylor College of Medicine
Scott, Kenneth L.
United States, Houston
Baylor College of Medicine
McFarland, Robert M.
United Kingdom, Newcastle
Wellcome Trust Centre for Mitochondrial Research
Taylor, Robert William
United Kingdom, Newcastle
Wellcome Trust Centre for Mitochondrial Research
Statistics
Citations: 132
Authors: 22
Affiliations: 7
Identifiers
Doi:
10.1016/j.ajhg.2013.07.017
ISSN:
00029297
e-ISSN:
15376605
Research Areas
Cancer
Genetics And Genomics
Maternal And Child Health