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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy
American Journal of Human Genetics, Volume 93, No. 3, Year 2013
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Description
Whole-exome sequencing and autozygosity mapping studies, independently performed in subjects with defective combined mitochondrial OXPHOS-enzyme deficiencies, identified a total of nine disease-segregating FBXL4 mutations in seven unrelated mitochondrial disease families, composed of six singletons and three siblings. All subjects manifested early-onset lactic acidemia, hypotonia, and developmental delay caused by severe encephalomyopathy consistently associated with progressive cerebral atrophy and variable involvement of the white matter, deep gray nuclei, and brainstem structures. A wide range of other multisystem features were variably seen, including dysmorphism, skeletal abnormalities, poor growth, gastrointestinal dysmotility, renal tubular acidosis, seizures, and episodic metabolic failure. Mitochondrial respiratory chain deficiency was present in muscle or fibroblasts of all tested individuals, together with markedly reduced oxygen consumption rate and hyperfragmentation of the mitochondrial network in cultured cells. In muscle and fibroblasts from several subjects, substantially decreased mtDNA content was observed. FBXL4 is a member of the F-box family of proteins, some of which are involved in phosphorylation-dependent ubiquitination and/or G protein receptor coupling. We also demonstrate that FBXL4 is targeted to mitochondria and localizes in the intermembrane space, where it participates in an approximately 400 kDa protein complex. These data strongly support a role for FBXL4 in controlling bioenergetic homeostasis and mtDNA maintenance. FBXL4 mutations are a recurrent cause of mitochondrial encephalomyopathy onset in early infancy. © 2013 The American Society of Human Genetics.
Authors & Co-Authors
Gai, Xiaowu
United States, Maywood
Loyola University Stritch School of Medicine
Ghezzi, Daniele
Italy, Milan
Besta's Institute
Johnson, Mark A.
United Kingdom, Cambridge
Mrc Mitochondrial Biology Unit
Biagosch, Caroline A.
Germany, Munich
Technische Universität München
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Shamseldin, Hanan E.
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Haack, Tobias Bernd
Germany, Munich
Technische Universität München
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Reyes, Aurelio
United Kingdom, Cambridge
Mrc Mitochondrial Biology Unit
Tsukikawa, Mai
United States, Philadelphia
University of Pennsylvania
Sheldon, Claire A.
United States, Philadelphia
University of Pennsylvania
Srinivasan, Satish
United States, Philadelphia
University of Pennsylvania
Gorza, Matteo
Germany, Munich
Technische Universität München
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Kremer, Laura S.
Germany, Munich
Technische Universität München
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Wieland, Thomas
Germany, Munich
Technische Universität München
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Strom, Tim Matthias
Germany, Munich
Technische Universität München
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Polyak, Erzsebet
United States, Philadelphia
University of Pennsylvania
Place, Emily
United States, Philadelphia
University of Pennsylvania
United States, Boston
Harvard Medical School
Consugar, Mark
United States, Houston
Baylor College of Medicine
Ostrovsky, Julian
United States, Philadelphia
University of Pennsylvania
Vidoni, Sara
United Kingdom, Cambridge
Mrc Mitochondrial Biology Unit
Robinson, Alan J.
United Kingdom, Cambridge
Mrc Mitochondrial Biology Unit
Wong, Leejun C.
United States, Houston
Baylor College of Medicine
Sondheimer, Neal J.
United States, Philadelphia
University of Pennsylvania
Salih, Mustafa Abdalla M.
Saudi Arabia, Riyadh
King Khalid University Hospital
Al Jishi, E.
Bahrain, Manama
Arabian Gulf University
Raab, Christopher P.
United States, Philadelphia
Jefferson Medical College
Bean, Charles
United States, Philadelphia
Jefferson Medical College
Furlan, Francesca
Italy, Monza
Mbbm Foundation A.o.s. Gerardo
Parini, Rossella
Italy, Monza
Mbbm Foundation A.o.s. Gerardo
Lamperti, Costanza
Italy, Milan
Besta's Institute
Mayr, Johannes Adalbert
Austria, Salzburg
Paracelsus Medizinische Privatuniversitat
Konstantopoulou, Vassiliki
Austria, Vienna
Medizinische Universität Wien
Huemer, Martina
Unknown Affiliation
Pierce, Eric A.
United States, Boston
Harvard Medical School
Meitinger, Thomas A.
Germany, Munich
Technische Universität München
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Freisinger, Peter
Germany, Reutlingen
Klinikum Reutlingen
Sperl, Wolfgang J.K.
Austria, Salzburg
Paracelsus Medizinische Privatuniversitat
Prokisch, Holger
Germany, Munich
Technische Universität München
Germany, Oberschleissheim
Helmholtz Center Munich German Research Center for Environmental Health
Alkuraya., Fowzan S.
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Saudi Arabia, Riyadh
College of Medicine Alfaisal University
Falk, Marni J.
United States, Philadelphia
University of Pennsylvania
Zeviani, Massimo
Italy, Milan
Besta's Institute
United Kingdom, Cambridge
Mrc Mitochondrial Biology Unit
Statistics
Citations: 141
Authors: 40
Affiliations: 17
Identifiers
Doi:
10.1016/j.ajhg.2013.07.016
ISSN:
00029297
e-ISSN:
15376605
Research Areas
Genetics And Genomics
Noncommunicable Diseases