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Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy.

ABSTRACT: Isolated cytochrome c oxidase (COX) deficiency is a prevalent cause of mitochondrial disease and is mostly caused by nuclear-encoded mutations in assembly factors while rarely by mutations in structural subunits. We hereby report a case of isolated COX deficiency manifesting with encephalomyopathy, hydrocephalus and hypertropic cardiomyopathy due to a missense p.R20C mutation in the COX6B1 gene, which encodes an integral, nuclear-encoded COX subunit. This novel mutation was predicted to be severe in silico. In accord, enzymatic activity was undetectable in muscle and fibroblasts, was severely decreased in lymphocytes and the COX6B1 protein was barely detectable in patient's muscle mitochondria. Complementation with the wild-type cDNA by a lentiviral construct restored COX activity, and mitochondrial function was improved by 5-aminoimidazole-4-carboxamide ribonucleotide, resveratrol and ascorbate in the patient's fibroblasts. We suggest that genetic analysis of COX6B1should be included in the investigation of isolated COX deficiency, including patients with cardiac defects. Initial measurement of COX activity in lymphocytes may be useful as it might circumvent the need for invasive muscle biopsy. The evaluation of ascorbate supplementation to patients with mutated COX6B1 is warranted.

SUBMITTER: Abdulhag UN

PROVIDER: S-EPMC4297913 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy.

Abdulhag Ulla Najwa UN Soiferman Devorah D Schueler-Furman Ora O Miller Chaya C Shaag Avraham A Elpeleg Orly O Edvardson Simon S Saada Ann A

European journal of human genetics : EJHG 20140430 2

Isolated cytochrome c oxidase (COX) deficiency is a prevalent cause of mitochondrial disease and is mostly caused by nuclear-encoded mutations in assembly factors while rarely by mutations in structural subunits. We hereby report a case of isolated COX deficiency manifesting with encephalomyopathy, hydrocephalus and hypertropic cardiomyopathy due to a missense p.R20C mutation in the COX6B1 gene, which encodes an integral, nuclear-encoded COX subunit. This novel mutation was predicted to be sever ...[more]

PMID: 24781756

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Project description:BackgroundInfantile-onset encephalopathy and hypertrophic cardiomyopathy caused by mitochondrial oxidative phosphorylation defects are genetically heterogeneous with defects involving both the mitochondrial and nuclear genomes.ObjectiveTo identify the causative genetic defect in two sisters presenting with lethal infantile encephalopathy, hypertrophic cardiomyopathy and optic atrophy.MethodsWe describe a comprehensive clinical, biochemical and molecular genetic investigation of two affected siblings from a consanguineous family. Molecular genetic analysis was done by a combined approach involving genome-wide autozygosity mapping and next-generation exome sequencing. Biochemical analysis was done by enzymatic analysis and Western blot. Evidence for mitochondrial DNA (mtDNA) instability was investigated using long-range and real-time PCR assays. Mitochondrial cristae morphology was assessed with transmission electron microscopy.ResultsBoth affected sisters presented with a similar cluster of neurodevelopmental deficits marked by failure to thrive, generalised neuromuscular weakness and optic atrophy. The disease progression was ultimately fatal with severe encephalopathy and hypertrophic cardiomyopathy. Mitochondrial respiratory chain complex activities were globally decreased in skeletal muscle biopsies. They were found to be homozygous for a novel c.1601T>G (p.Leu534Arg) mutation in the OPA1 gene, which resulted in a marked loss of steady-state levels of the native OPA1 protein. We observed severe mtDNA depletion in DNA extracted from the patients' muscle biopsies. Mitochondrial morphology was consistent with abnormal mitochondrial membrane fusion.ConclusionsWe have established, for the first time, a causal link between a pathogenic homozygous OPA1 mutation and human disease. The fatal multisystemic manifestations observed further extend the complex phenotype associated with pathogenic OPA1 mutations, in particular the previously unreported association with hypertrophic cardiomyopathy. Our findings further emphasise the vital role played by OPA1 in mitochondrial biogenesis and mtDNA maintenance.

Dataset Information

Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy.

Publications

Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy.

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