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

We investigated two unrelated children with an isolated defect of mitochondrial complex III activity. The clinical picture was characterized by a progressive encephalopathy featuring early-onset developmental delay, spasticity, seizures, lactic acidosis, brain atrophy and MRI signal changes in the basal ganglia. Both children were compound heterozygotes for novel mutations in the human bc1 synthesis like (BCS1L) gene, which encodes an AAA mitochondrial protein putatively involved in both iron homeostasis and complex III assembly. The pathogenic role of the mutations was confirmed by complementation assays, using a DeltaBcs1 strain of Saccharomyces cerevisiae. By investigating complex III assembly and the structural features of the BCS1L gene product in skeletal muscle, cultured fibroblasts and lymphoblastoid cell lines from our patients, we have demonstrated, for the first time in a mammalian system, that a major function of BCS1L is to promote the maturation of complex III and, more specifically, the incorporation of the Rieske iron-sulfur protein into the nascent complex. Defective BCS1L leads to the formation of a catalytically inactive, structurally unstable complex III. We have also shown that BCS1L is contained within a high-molecular-weight supramolecular complex which is clearly distinct from complex III intermediates.
Hum Mol Genet 2007 May 15
PMID:Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy. 1740 14

Recently, many studies seen concerning the expression and distribution of aquaporins and K channels in the central nervous system, and their physiological and pathophysiologic roles in water and ion homeostasis. Whereas most data were collected on aquaporin-4 (AQP4) in astrocytes, only little attention was paid to AQP9 which is a water channel transporting glycerol, mannitol, and urea as well. This is the first study describing AQP9 in human brain and human brain tumors. For comparison, we also investigated the immunohistochemical distribution of AQP9 in the rat glioma RG2. Whereas in the normal rat brain AQP9 is only weakly expressed by astrocytes, the anti-AQP9 immunoreactivity was found to be increased at the tumor border, but not within the tumor. In contrast, in human glioblastoma, most glioma cells throughout the tumor revealed a strong anti-AQP9 immunoreactivity across the whole surface of the cell. In the discussion, the increase of the anti-AQP9 immunoreactivity in glioma cells is suggested to reflect an upregulation and to counteract the glioma-associated lactic acidosis by clearance of glycerol and lactate from the extracellular space. In addition, the increased level of AQP9 immunoreactivity could be involved in the energy metabolism of the glioma and/or surrounding neuronal cells.
Appl Immunohistochem Mol Morphol 2007 Jun
PMID:Expression of the water channel protein aquaporin-9 in malignant brain tumors. 1752 33

Pyruvate dehydrogenase complex (PDC) deficiencies are a major cause of primary lactic acidosis. Most cases result from mutations of the gene for the pyruvate dehydrogenase E1alpha subunit (PDHA1), with fewer cases resulting from mutations in genes for E3, E3-binding protein, E2, and the E1beta subunit (PDHB). We have found four cases of PDHB mutations among 83 analyzed cases of PDC deficiency. In this series, PDHB mutations were found to be about 10% as frequent as PDHA1 mutations. All cases were diagnosed by low PDC activity, with normal E2 and E3 activities. These included a 6.5-year-old male (consanguineous, homozygous R36C); a neonatal female who died soon after birth, (compound heterozygous C306R/D319V), a 26-year-old female (heterozygous I142M/W165S), and a 13month old female (consanguineous, homozygous Y132C) who is a sibling of a previously published case. Their ethnic background is diverse (Caucasian, Arab, and African American descent). All cases had lactic acidosis and developmental delay. Three cases had agenesis of the corpus callosum, seizures, and hypotonia; one died within the first year of life. These clinical findings are similar to those of PDHA1 deficiency, except that ataxia was more frequent in PDHA1 cases and consanguinity was found only in PDHB families. PDC activity in lymphocytes from six parents is normal, who all are heterozygous carriers for the respective mutations. Immunoreactivity of E1beta was markedly reduced in one case and showed a slightly larger form of E1beta in one case. Computer analysis predicts that: R36C affects the interaction of several amino acids resulting in conformational change, C306R affects interaction of the two beta subunits, D319 is in the interface of E1 and E2, I142M affects conformation around a K ion affecting stability of the beta subunit, W165S affects hydrophobic interaction between the beta subunits, and Y132C affects interaction between the beta subunits. All of these residues are conserved in E1beta across species, and Y132 is also conserved in other TPP-requiring enzymes. These observations support the conclusion that these are pathogenic mutations.
Mol Genet Metab 2008 Apr
PMID:Mutations of the E1beta subunit gene (PDHB) in four families with pyruvate dehydrogenase deficiency. 1816 39

We describe the mapping and identification of the gene for hereditary myopathy with lactic acidosis (HML). HML is characterized by low physical performance, resulting in physical exertion that causes early exhaustion, dyspnoea and palpitations. Using an autosomal recessive mode of inheritance, we mapped the trait to chromosome 12q23.3-24.11, with a maximum lod score of 5.26. The 1.6-Mb disease-critical region contained one obvious candidate gene-ISCU-specifying a protein involved in iron-sulphur cluster assembly. IscU is produced in two isoforms; one cytosolic and one mitochondrial, coded for by different splice variants of the ISCU gene. Mutational analysis of all exon and intron sequences as well as 1000 bp of the promoter of the ISCU gene revealed one intron mutation that was specific for the disease haplotype. The mutation is located in a region with homology to the interferon-stimulated response element (ISRE), but we could not see any effect of the mutation on expression levels in vitro or in vivo. We did, however, observe a drastic difference in the splicing pattern between patients and controls. In controls the mRNA was, as expected, mainly in the mitochondrial form, while in the patients a larger mRNA transcript was predominant. Sequencing of the product revealed that the mutation activates cryptic splice sites in intron 5 resulting in aberrant mRNA containing 100 bp of the intron. To conclude, our data strongly suggest that an intron mutation in the ISCU gene, leading to incorrectly spliced mRNA, is the cause of myopathy with lactic acidosis in this family.
Hum Mol Genet 2008 Jun 01
PMID:Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect. 1829 49

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a genetically heterogeneous mitochondrial disorder with variable clinical symptoms. Here, from the sequencing of the entire mitochondrial genome, we report a Korean MELAS family harboring two homoplasmic missense mutations, which were reported 9957T>C (Phe251Leu) transition mutation in the cytochrome c oxidase subunit 3 (COX3) gene and a novel 13849A>C (Asn505His) transversion mutation in the NADH dehydrogenase subunit 5 (ND5) gene. Neither of these mutations was found in 205 normal controls. Both mutations were identified from the proband and his mother, but not his father. The patients showed cataract symptom in addition to MELAS phenotype. We believe that the 9957T>C mutation is pathogenic, however, the 13849A>C mutation is of unclear significance. It is likely that the 13849A>C mutation might function as the secondary mutation which increase the expressivity of overlapping phenotypes of MELAS and cataract. This study also demonstrates the importance of full sequencing of mtDNA for the molecular genetic understanding of mitochondrial disorders.
Exp Mol Med 2008 Jun 30
PMID:A MELAS syndrome family harboring two mutations in mitochondrial genome. 1858 74

The majority of patients with MELAS (mitochondrial encephalomyophathy, lactic acidosis, stroke-like episodes) carry a heteroplasmic A3243G mutation in the mitochondrial tRNA(Leu(UUR)). The mutation prevents modification of the wobble U base, impairing translation at UUA and UUG codons; however, whether this results in amino acid misincorporation in the mitochondrial translation products remains controversial. We tested this hypothesis in homoplasmic mutant myoblasts isolated from a MELAS patient and investigated whether overexpression of the mitochondrial translation elongation factors could suppress the translation defect. Blue-Native gel electrophoretic analysis demonstrated an almost complete lack of assembly of respiratory chain complexes I, IV and V in MELAS myoblasts. This phenotype could be partially suppressed by overexpression of EFTu or EFG2 but not EFTs or EFG1. Despite the severity of the assembly defect, overall mitochondrial protein synthesis was only moderately affected, but some anomalously migrating translation products were present. Pulse-chase labeling showed reduced stability of all mitochondrial translation products consistent with the assembly defect. Labeling patterns of the translation products were similar with [(3)H]-leucine or [(3)H]-phenylalanine, showing that loss of the wobble U modification did not permit decoding of UUY codons; however, endoproteinase fingerprint analysis showed clear evidence of amino acid misincorporation in three polypeptides: CO III, CO II and ATP6. Taken together, these data demonstrate that the A3243G mutation produces both loss- and gain-of-function phenotypes, explaining the apparent discrepancy between the severity of the translation and respiratory chain assembly defects, and suggest a function for EFG2 in quality control of translation elongation.
Hum Mol Genet 2008 Dec 01
PMID:The A3243G tRNALeu(UUR) MELAS mutation causes amino acid misincorporation and a combined respiratory chain assembly defect partially suppressed by overexpression of EFTu and EFG2. 1875 47

Members of the peroxisome proliferator-activated receptor gamma coactivator (PGC) family are potent inducers of mitochondrial biogenesis. We have tested the potential effect of increased mitochondrial biogenesis in cells derived from patients harboring oxidative phosphorylation defects due to either nuclear or mitochondrial DNA mutations. We found that the PGC-1alpha and/or PGC-1beta expression improved mitochondrial respiration in cells harboring a complex III or IV deficiency as well as in transmitochondrial cybrids harboring mitochondrial encephalomyopathy lactic acidosis and stroke A3243G tRNA((Leu)UUR) gene mutation. The respiratory function improvement was found to be associated with increased levels of mitochondrial components per cell, although this increase was not homogeneous. These results reinforce the concept that increased mitochondrial biogenesis is a promising venue for the treatment of mitochondrial diseases.
Hum Mol Genet 2009 May 15
PMID:PGC-1alpha/beta induced expression partially compensates for respiratory chain defects in cells from patients with mitochondrial disorders. 1929 90

Glycogen storage disease type I (GSD I) is caused by inherited defects of the glucose 6-phosphatase complex, resulting in fasting hypoglycemia, lactic acidosis, hyperuricemia and hyperlipidemia. Sixteen out of 26 (61.5%) GSD I patients in our study had suboptimal levels (<30 ng/ml) of 25-hydroxyvitamin-D (25(OH)D) despite supplementation of vitamin D and/or vitamin D + calcium based on WHO standards in 24/26 (92.3%) patients. The restrictive nature of the GSD I diet, metabolic derangements and intestinal malabsorption seen in GSD I are possible reasons for the observed hypovitaminosis D. Our results suggest that measurement of 25(OH)D should be considered in the routine evaluation of GSD I patients.
Mol Genet Metab 2010 Apr
PMID:Hypovitaminosis D in glycogen storage disease type I. 2006 Mar 50

Dichloroacetate (DCA) is a metabolic modulator for the treatment of lactic acidosis and inherited mitochondrial diseases. A recent study showed that DCA treatment could induce apoptosis in many kinds of tumor cell lines via mitochondrial apoptotic pathway while sparing normal cells. ONYX-015 (dl 1520) is one of the oncolytic adenoviruses developed by the deletion of E1B-55kD gene of type 5 adenoviral DNA, and it replicates efficiently and selectively in tumor cells. ZD55-IL-24, an E1B-55kD deleted oncolytic adenovirus carrying interleukin-24 (IL-24, also called melanoma differentiation associated gene-7), had showed potent antitumor efficacy in a variety of tumor cells and exerted no apparent toxicity on normal cells. Given both the good therapeutic effect and low toxicity of these agents, here we investigated whether DCA in combination with ZD55-IL-24 or ONYX-015 could have more efficient antitumor activity in vitro experiments. Therefore, we tested the cytotoxicity of combination therapy in normal hepatic cells L-02 and QSG-7701 using the MTT assay. Our results showed that DCA combined with ONYX-015 or ZD55-IL-24 exhibited more potent antitumor activity than DCA or virus alone, and the combination treatment did not have superimposed toxicities in normal cells. Thus, a novel combination therapy associating oncolytic adenoviruses with relatively low toxic drug without severe side effects was proposed.
Mol Cell Biochem 2010 Jul
PMID:Dichloroacetate (DCA) enhances tumor cell death in combination with oncolytic adenovirus armed with MDA-7/IL-24. 2016 5

Mutations in mitochondrial tRNA genes are associated with a wide spectrum of human diseases. In particular, the tRNA(Leu(UUR)) A3243G mutation causes mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms (MELAS) and 2% of cases of type 2 diabetes. The primary defect in this mutation was an inefficient aminoacylation of the tRNA(Leu(UUR)). In the present study, we have investigated the molecular mechanism of the A3243G mutation and whether the overexpression of human mitochondrial leucyl-tRNA synthetase (LARS2) in the cytoplasmic hybrid (cybrid) cells carrying the A3243G mutation corrects the mitochondrial dysfunctions. Human LARS2 localizes exclusively to mitochondria, and LARS2 is expressed ubiquitously but most abundantly in tissues with high metabolic rates. We showed that the alteration of aminoacylation tRNA(Leu(UUR)) caused by the A3243G mutation led to mitochondrial translational defects and thereby reduced the aminoacylated efficiencies of tRNA(Leu(UUR)) as well as tRNA(Ala) and tRNA(Met). We demonstrated that the transfer of human mitochondrial leucyl-tRNA synthetase into the cybrid cells carrying the A3243G mutation improved the efficiency of aminoacylation and stability of mitochondrial tRNAs and then increased the rates of mitochondrial translation and respiration, consequently correcting the mitochondrial dysfunction. These findings provide new insights into the molecular mechanism of maternally inherited diseases and a step toward therapeutic interventions for these disorders.
Mol Cell Biol 2010 May
PMID:Human mitochondrial leucyl-tRNA synthetase corrects mitochondrial dysfunctions due to the tRNALeu(UUR) A3243G mutation, associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms and diabetes. 2884 73


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