Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.9.3.1 (cytochrome oxidase)
 8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Defects in mitochondrial translation are associated with a remarkable, but unexplained diversity of clinical phenotypes. Here we have investigated the molecular basis for tissue specificity in patients with a fatal hepatopathy due to mutations in the mitochondrial translation elongation factor EFG1. Blue-native gel electrophoresis revealed unique, tissue-specific patterns in the nature and severity of the defect. Liver was the most severely affected tissue, with less than 10% residual assembly of complexes I and IV, and a 50% decrease in complex V. Skeletal muscle showed a 50% reduction in complex I, and complexes IV and V were 20% of control. In fibroblasts, complexes I and IV were 20% of control, and there was a 40-60% reduction in complexes III and V. In contrast, except for a 50% decrease in complex IV, all complexes were near normal in heart. The severity of the defect paralleled the steady-state level of the mutant EFG1 protein, which varied from 60% of control in heart to undetectable in liver. The ratio of translation elongation factors EFTu:EFTs increased from 1:6 to 1:2 in patient heart, whereas in liver it decreased from 1:1 to 1:4. Over-expression of either EFTu or EFTs in control and patient fibroblasts produced dominant negative effects, indicating that the relative abundance of these factors is an important determinant of translation efficiency. Our results demonstrate marked differences among tissues in the organization of the mitochondrial translation system and its response to dysfunction, and explain the severe hepatopathy, but normal cardiac function in EFG1 patients.
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PMID:The molecular basis for tissue specificity of the oxidative phosphorylation deficiencies in patients with mutations in the mitochondrial translation factor EFG1. 1663 85

Multiple respiratory chain deficiencies represent a common cause of mitochondrial diseases. We report two novel GFM1 mutations in two unrelated patients with encephalopathy and liver failure respectively. The first patient had intrauterine growth retardation, seizures, encephalopathy and developmental delay. Brain MRI showed hypoplasia of the vermis and severe pontine atrophy of the brainstem that were similar to those reported in patients with mitochondrial translation deficiencies. The second patient had liver failure with hypoglycemia. Respiratory chain analysis showed a complex IV deficiency in muscle of both patients. A 10K SNP genotyping detected several regions of homozygosity in the two patients. In vitro translation deficiency prompted us to study genes involved in mitochondrial translation. Therefore, we sequenced the GFM1 gene, encoding the mitochondrial translation factor EFG1, included in a shared homozygous region and identified two different homozygous mutations (R671C and L398P). Modeling studies of EFG1 protein suggested that the R671C mutation disrupts an inter-subunit interface and could locally destabilize the mutant protein. The second mutation (L398P) disrupted the H-bond network in a rich-beta-sheet domain, and may have a dramatic effect on local structure. GFM1 mutations have been seldom reported and are associated with different clinical presentation. By modeling the structure of the protein and the position of the various mutations we suggest that the clinical phenotypes of the patients could be related to the localization of the mutations.
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PMID:Toward genotype phenotype correlations in GFM1 mutations. 2198 55