Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance.
Am J Hum Genet
; 93(3): 471-81, 2013 Sep 05.
Article
em En
| MEDLINE
| ID: mdl-23993193
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
DNA Mitocondrial
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Encefalomiopatias Mitocondriais
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Predisposição Genética para Doença
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Ubiquitina-Proteína Ligases
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Proteínas F-Box
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Mutação
Limite:
Child
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Child, preschool
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Female
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Humans
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Infant
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Male
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Newborn
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article