Complex I deficiency, due to NDUFAF4 mutations, causes severe mitochondrial dysfunction and is associated to early death and dysmorphia
| Autor: | Laura Gort, Frederic Tort, María Teresa García-Silva, Luis Aldámiz-Echevarría, Olatz Ugarteburu, Judit García-Villoria, Antonia Ribes |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Mitochondrial Diseases Cell Respiration Nonsense mutation Encephalopathy Cardiomyopathy Mitochondrion medicine.disease_cause Consanguinity 03 medical and health sciences 0302 clinical medicine Internal medicine Exome Sequencing Humans Point Mutation Medicine Child Molecular Biology Cells Cultured Mutation business.industry High-Throughput Nucleotide Sequencing Hyperammonemia Cell Biology Fibroblasts medicine.disease Pedigree 030104 developmental biology Endocrinology Child Preschool Lactic acidosis Molecular Medicine Calmodulin-Binding Proteins Female business 030217 neurology & neurosurgery Urine organic acids |
| Zdroj: | Mitochondrion. 55:78-84 |
| ISSN: | 1567-7249 |
| DOI: | 10.1016/j.mito.2020.09.003 |
| Popis: | Pathogenic mutations in NDUFAF4 have been reported in very few cases. Here we present new data to further delineate the phenotypic spectrum of NDUFAF4 deficiency. We describe two siblings presenting with facial dysmorphia and lactic acidosis in the neonatal period. Later on, they developed fatal early encephalopathy with apneic episodes, irritability, central hypoventilation, liver involvement and hyperammonemia. Abnormality of the cerebral white matter was demonstrated in one case, and cardiomyopathy in the other. Urine organic acid profile showed an increased excretion of lactate, Krebs cycle metabolites and 3-methylglutaconate. Whole-exome sequencing identified a novel homozygous nonsense mutation in NDUFAF4 (c.478G > T; p.Glu160Ter), encoding a mitochondrial complex I assembly factor. The disruptive effect of the mutation was corroborated by the absence of NDUFAF4 expression in patient fibroblasts. OXPHOS assembly studies demonstrated almost undetectable levels of fully assembled complex I and complex I–containing supercomplexes and an abnormal accumulation of SCIII2IV1 supercomplexes. Morphologically, fibroblasts showed rounder mitochondria and a diminished degree of branching of the mitochondrial network. Cellular respiratory capacity in fibroblasts was also markedly reduced. In sum, we provide insights into the physiopathological mechanisms underlying NDUFAF4 deficiency and expand the knowledge about the clinical and biochemical spectrum of this disorder. |
| Databáze: | OpenAIRE |
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