RESUMO
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.
Assuntos
DNA Mitocondrial/genética , Proteínas F-Box/genética , Predisposição Genética para Doença , Encefalomiopatias Mitocondriais/genética , Mutação/genética , Ubiquitina-Proteína Ligases/genética , Acidose Láctica/complicações , Acidose Láctica/genética , Acidose Láctica/patologia , Sequência de Bases , Criança , Pré-Escolar , Segregação de Cromossomos/genética , Transporte de Elétrons/genética , Proteínas F-Box/química , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Dosagem de Genes/genética , Genes Recessivos/genética , Humanos , Lactente , Recém-Nascido , Masculino , Encefalomiopatias Mitocondriais/complicações , Encefalomiopatias Mitocondriais/patologia , Dados de Sequência Molecular , Músculo Esquelético/patologia , Fosforilação Oxidativa , Linhagem , Transporte Proteico , Ubiquitina-Proteína Ligases/químicaRESUMO
Microcephaly-capillary malformation syndrome (MIC-CAP syndrome) is a newly recognized autosomal recessive congenital neurocutaneous central nervous system disorder characterized by severe microcephaly, early-onset seizures, profound psychomotor disability, and multiple cutaneous capillary lesions. In addition, affected patients have variable dysmorphic facial features and hypoplastic distal phalanges. It is distinctively caused by mutations in a newly characterized gene, STAMBP, encoding the deubiquitinating (DUB) isopeptidase that has a key role in cell surface receptor-mediated endocytosis and sorting. Herein, we describe an Arab family of two siblings with classic features of MIC-CAP syndrome that harbor a novel predicted splice mutation in STAMBP, which additionally display previously unreported findings of congenital hypothyroidism and alopecia areata.