Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this paper, we describe a distinct clinical subtype of 3-methylglutaconic aciduria. 3-Methylglutaconic aciduria is a group of different metabolic disorders biochemically characterized by increased urinary excretion of 3-methylglutaconic acid. We performed biochemical and genetic investigations, including urine organic acid analysis, NMR spectroscopy, measurement of 3-methylglutaconyl-CoA hydratase activity, cardiolipin levels, OPA3 gene analysis and measurement of the oxidative phosphorylation in four female patients with 3-methylglutaconic aciduria. 3-Methylglutaconic aciduria type I, Barth syndrome, and Costeff syndrome were excluded as the activity of 3-methylglutaconyl-CoA hydratase, the cardiolipin levels, and molecular analysis of the OPA3 gene, respectively, showed no abnormalities. The children presented with characteristic association of hearing loss and the neuro-radiological evidence of Leigh disease. They also had neonatal hypotonia, recurrent lactic acidemia, episodes with hypoglycemia and severe recurrent infections, feeding difficulties, failure to thrive, developmental delay, and progressive spasticity with extrapyramidal symptoms. Our patients were further biochemically characterized by a mitochondrial dysfunction and persistent urinary excretion of 3-methylglutaconic acid.
Mol Genet Metab 2006 May
PMID:Association of 3-methylglutaconic aciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome (MEGDEL association) in four patients with a disorder of the oxidative phosphorylation. 1652 7

Unlike many pathogenic mitochondrial DNA mutations, the T8993G mutation associated with Leigh syndrome (LS) and neurogenic muscle weakness, ataxia, retinitis pigmentosa (NARP) typically shows little variation in mutant load between different tissue types. We describe the molecular and clinical findings in a family with variable disease severity and tissue T8993G mutant loads. Real-time ARMS qPCR testing showed that two brothers with features of NARP and LS had high mutant loads (>90%) in all tissues tested, similar to previously reported cases. Their sister, who has mild speech delay but attends normal school, was found to have a relatively high mutant load (mean 93%) in tissues derived from endoderm (buccal mucosa) and mesoderm (blood and skin fibroblasts). However, in tissue derived from ectoderm (hair bulbs), she carried a considerably lower proportion of mutant mtDNA. Because both surface ectoderm, which gives rise to outer epithelia and hair, and neuroectoderm, which gives rise to the central nervous system, are derived from ectoderm, it is tempting to speculate that the mutant load detected in the oligosymptomatic sister's hair bulbs is a reflection of the brain mutant load. We conclude that significant variation in tissue mutant load may occur in at least some individuals that harbor the T8993G mutation. This adds additional complexity to genetic counseling and prenatal diagnosis in such instances. Given the shared embryonic origin of hair bulbs and brain, we recommend performing hair bulb mtDNA analysis in asymptomatic or oligosymptomatic individuals that have high blood mutant loads in order to understand better the genotype-phenotype correlations related to the T8993G mutation.
Mol Genet Metab 2006 Aug
PMID:Molecular-clinical correlations in a family with variable tissue mitochondrial DNA T8993G mutant load. 1654 28

We report a patient with relatively mild Leigh syndrome and mitochondrial respiratory chain complex II deficiency caused by a homozygous G555E mutation in the nuclear encoded flavoprotein subunit of succinate dehydrogenase. This mutation has previously been reported in a lethal-infantile presentation of complex II deficiency. Such marked phenotypic heterogeneity, although typical of heteroplasmic mutations in the mitochondrial genome, is unusual for nuclear mutations. Comparable activities and stability of mitochondrial respiratory chain enzymes were demonstrated in both patients, so other reasons for the phenotypic variability are considered.
Mol Genet Metab 2006 Nov
PMID:Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II. 1679 39

We describe a novel mitochondrial ND2 mutation (T4681C) in a patient presenting with Leigh Syndrome. Biochemical analyses revealed a low isolated complex I activity in patient's fibroblasts, blood and skeletal muscle. Mutant transmitochondrial cybrid clones retained the specific complex I defect, demonstrating the mitochondrial genetic origin of the disease. The mutation leads to a L71P substitution at an evolutionary conserved amino acid stretch. By two-dimensional blue native electrophoresis (2D-BN-SDS-PAGE), decreased complex I levels were observed together with an accumulation of specific assembly intermediates, suggesting that the mutation disturbs the complex I assembly pathway.
Mol Genet Metab 2007 Jan
PMID:Mutated ND2 impairs mitochondrial complex I assembly and leads to Leigh syndrome. 1699 90

Leigh syndrome associated with cytochrome c oxidase (COX) deficiency is a mitochondrial disorder usually caused by mutations of SURF1, a gene encoding a putative COX assembly factor. We present here a Surf1-/- recombinant mouse obtained by inserting a loxP sequence in the open reading frame of the gene. The frequency of -/-, +/+ and +/- genotypes in newborn mice followed a mendelian distribution, indicating that the ablation of Surf1 is compatible with postnatal survival. The biochemical and assembly COX defect was present in Surf1(loxP)-/- mice, but milder than in humans. Surprisingly, not only these animals failed to show spontaneous neurodegeneration at any age, but they also displayed markedly prolonged lifespan, and complete protection from Ca(2+)-dependent neurotoxicity induced by kainic acid. Experiments on primary neuronal cultures showed markedly reduced rise of cytosolic and mitochondrial Ca(2+) in Surf1(loxP)-/- neurons, and reduced mortality, compared to controls. The mitochondrial membrane potential was unchanged in KO versus wild-type neurons, suggesting that the effects of the ablation of Surf1 on Ca(2+) homeostasis, and possibly on longevity, may be independent, at least in part, from those on COX assembly and mitochondrial bioenergetics.
Hum Mol Genet 2007 Feb 15
PMID:Increased longevity and refractoriness to Ca(2+)-dependent neurodegeneration in Surf1 knockout mice. 1721 Jun 71

Defects in NADH:ubiquinone oxidoreductase, the complex I of the mitochondrial respiratory chain represents the most frequent cause of mitochondrial diseases and is associated with a wide clinical spectrum varying from severe lactic acidosis in infants to muscle weakness in adults. Here, we report a patient with Leigh syndrome (LS), born to consanguineous parents, with severe complex I defect and a novel mutation in the NDUFS7 gene subunit. The homozygous mutation at nucleotide (nt) 434 G>A resulted in the modification of the arginine 145 to histidine in a highly conserved region of the protein. Parents were heterozygous carriers for this mutation. The mutation was absent from over than 100 healthy controls from the same ethnic origin. Identifying nuclear mutations as a cause of respiratory chain disorders will enhance the possibility of prenatal diagnosis and help us to understand how moleculardefects can lead to complex I deficiency.
Mol Genet Metab 2007 Apr
PMID:A novel mutation in the human complex I NDUFS7 subunit associated with Leigh syndrome. 1727 78

Leigh's syndrome is a complex neurological disease with little known correlation between causes and symptoms. Mutations in pyruvate dehydrogenase and electron transport chain complexes have been associated with this syndrome, although the identification of affected enzymes is difficult, if not impossible, with non-invasive clinical tests. In this study, isotopomer analysis is used to characterize the metabolic phenotype of normal and Leigh's syndrome fibroblasts (GM01503), thereby identifying affected enzymes in the diseased cells. Fibroblasts are grown with DMEM media enriched with (13)C labeled glucose. Amino acids from media and proteins as well as lactate are analyzed with GC-MS to identify their label distributions. A computational model accounting for all major pathways in fibroblast metabolism (including 430 metabolites and 508 reactions) is built to determine the metabolic steady states of the normal and Leigh's cell lines based on measured substrate uptake and secretion rates and isotopomer data. Results show that (i) Leigh's syndrome affected cells have slower metabolism than control fibroblasts as evidenced by their overall slower substrate utilization and lower secretion of end products; (ii) intracellular fluxes predicted by the models, some of which are validated by biochemical studies published in the literature, show that the respiratory chain in Leigh's affected cells can produce ATP at a similar rate as the controls, but with a more restricted flux range; and (iii) mutations causing the defects observed in the Leigh's cells are likely to be in succinate cytochrome c reductase.
Mol Genet Metab 2007 May
PMID:Systems analysis of energy metabolism elucidates the affected respiratory chain complex in Leigh's syndrome. 1733 15

Complex I deficiency is a frequent cause of mitochondrial disease as it accounts for one third of these disorders. By genotyping several putative disease loci using microsatellite markers we were able to describe a new NDUFS7 mutation in a consanguineous family with Leigh syndrome and isolated complex I deficiency. This mutation lies in the first intron of the NDUFS7 gene (c.17-1167 C>G) and creates a strong donor splice site resulting in the generation of a cryptic exon. This mutation is predicted to result in a shortened mutant protein of 41 instead of 213 amino acids containing only the first five amino acids of the normal protein. Analysis of the assembly state of the respiratory chain complexes under native condition revealed a marked decrease of fully assembled complex I while the quantity of the other complexes was not altered. These results report the first intronic NDUFS7 gene mutation and demonstrate the crucial role of NDUFS7 in the biogenesis of complex I.
Mol Genet Metab
PMID:A novel mutation of the NDUFS7 gene leads to activation of a cryptic exon and impaired assembly of mitochondrial complex I in a patient with Leigh syndrome. 1760 71

Cell survival and energy production requires a functional mitochondrial respiratory chain. Biogenesis of cytochrome c oxidase (COX), the last enzyme of the mitochondrial respiratory chain, is a very complicated process and requires the assistance of a large number of accessory factors. Defects in COX assembly alter cellular respiration and produce severe human encephalomyopathies. Mutations in SURF1, a COX assembly factor of exact unknown function, produce Leigh's syndrome (LS), the most frequent cause of COX deficiency in infants. In the yeast Saccharomyces cerevisiae, deletion of the SURF1 homologue SHY1 results in a similar COX deficiency. In order to identify genetic modifiers of the shy1 mutant phenotype, we have explored for genetic interactions involving SHY1. Here we report that overexpression of Hap4p, the catalytic subunit of the CCAAT binding transcriptional activator Hap2/3/4/5p complex, suppresses the respiratory defect of yeast shy1 mutants by increasing the expression of nuclear-encoded COX subunits that interact with the mitochondrially encoded Cox1p. Analogously, overexpression of the Hap complex human homologue NF-YA/B/C transcription complex in SURF1-deficient fibroblasts from an LS patient efficiently rescues their COX deficiency.
Hum Mol Genet 2008 Mar 15
PMID:Transcriptional activators HAP/NF-Y rescue a cytochrome c oxidase defect in yeast and human cells. 1804 76

The mitochondrial 13513G>A (D393N) mutation in the ND5 subunit of the respiratory chain complex I was initially described in association with MELAS syndrome. Recent observations have linked this mutation to Leigh disease. We screened for the 13513G>A mutation in a cohort of 265 patients with Leigh and Leigh-like disease. The mutation was found in a total of 5 patients. An additional patient who had clinical presentation consistent with a Leigh-like phenotype but with a normal brain MRI was added to the cohort. None of an additional 88 patients meeting MELAS disease criteria, nor 56 patients with respiratory chain deficiency screened for the 13513G>A were found positive for the mutation. The most frequent clinical manifestations in our patients were hypotonia, ocular and cerebellar involvement. Low mutation heteroplasmy in the range of 20-40% was observed in all 6 patients. This observation is consistent with the previously reported low heteroplasmy of this mutation in some patients with the 13513G>A mutation and complex I deficiency. However, normal complex I activity was observed in two patients in our cohort. As most patients with Leigh-like disease and the 13513G>A mutation have been described with complex I deficiency, this report adds to the previously reported subset of patients with normal respiratory complex function. We conclude that in any patient with Leigh or Leigh-like disease, testing for the 13513G>A mutation is clinically relevant and low mutant loads in blood or muscle may be considered pathogenic, in the presence of normal respiratory chain enzyme activities.
Mol Genet Metab 2008 Aug
PMID:The mitochondrial 13513G>A mutation is associated with Leigh disease phenotypes independent of complex I deficiency in muscle. 1849 10


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>