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Anne M Remes

Publications and source records attributed to Anne M Remes.

6 recordsLinked to original sources
PubMed2006

Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF.

The stability and transcriptional activity of the hypoxia-inducible factors (HIFs) are regulated by two oxygen-dependent events that are catalyzed by three HIF prolyl 4-hydroxylases (HIF-P4Hs) and one HIF asparaginyl hydroxylase (FIH). We have studied possible links between metabolic pathways and HIF hydroxylases by analyzing the abilities of citric acid cycle intermediates to inhibit purified human HIF-P4Hs and FIH. Fumarate and succinate were identified as in vitro inhibitors of all three HIF-P4Hs, fumarate having K(i) values of 50-80 microM and succinate 350-460 microM, whereas neither inhibited FIH. Oxaloacetate was an additional inhibitor of all three HIF-P4Hs with K(i) values of 400-1000 microM and citrate of HIF-P4H-3, citrate being the most effective inhibitor of FIH with a K(i) of 110 microM. Culturing of cells with fumarate diethyl or dimethyl ester, or a high concentration of monoethyl ester, stabilized HIF-1alpha and increased production of vascular endothelial growth factor and erythropoietin. Similar, although much smaller, changes were found in cultured fibroblasts from a patient with fumarate hydratase (FH) deficiency and upon silencing FH using small interfering RNA. No such effects were seen upon culturing of cells with succinate diethyl or dimethyl ester. As FIH was not inhibited by fumarate, our data indicate that the transcriptional activity of HIF is quite high even when binding of the coactivator p300 is prevented. Our data also support recent suggestions that the increased fumarate and succinate levels present in the FH and succinate dehydrogenase-deficient tumors, respectively, can inhibit the HIF-P4Hs with consequent stabilization of HIF-alphas and effects on tumor pathology.

Cell Line↗
PubMed2005

Sequence analysis of nuclear genes encoding functionally important complex I subunits in children with encephalomyopathy.

Complex I has a vital role in the energy production of the cell, and the clinical spectrum of complex I deficiency varies from severe lactic acidosis in infants to muscle weakness in adults. It has been estimated that the cause of complex I deficiency, especially in children, is often a mutation in the nuclear-encoded genes and, more rarely, in the genes encoded by mitochondrial DNA. We sequenced nine complex I subunit coding genes, NDUFAB1, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1 and NDUFV2, in 13 children with defined complex I deficiency. Two novel substitutions were found: a synonymous replacement 201A>T in NDUFV2 and a non-synonymous base exchange 52C>T in NDUFS8. The 52C>T substitution produced the replacement Arg18Cys in the leading peptide of the TYKY subunit. This novel missense mutation was found as a heterozygote in one patient and her mother, but not among 202 healthy controls nor among 107 children with undefined encephalomyopathy. Bioinformatic analyses suggested that Arg18Cys could lead to marked changes in the physicochemical properties of the mitochondrial-targeting peptide of TYKY, but we could not see changes in the assembly or activity of complex I or in the transcription of NDUFS8 in the fibroblasts of our patient. We suggest that Arg18Cys in the leading peptide of the TYKY subunit is not solely pathogenic, and that other genetic factors contribute to the disease-causing potential of this mutation.

Alleles↗
PubMed2005

Comprehension of before and after in frontotemporal degeneration.

Frontotemporal lobar degeneration (FTLD) is a dementia syndrome with behavioural problems and deterioration of language functions. The other cognitive domains are relatively preserved for at least the first two years of the disease. We studied the ability of patients with FTLD to understand before and after constructions expressed in Finnish. Ten patients and eight controls were presented eight sentences with different relations and asked questions to test their comprehension. The results showed that the patients generally found after constructions more difficult. The difficulty was not, however, related to normal ageing, as was shown by the performance of the control group.

Aged↗
PubMed2004

A novel mutation of the fumarase gene in a family with autosomal recessive fumarase deficiency.

Fumarase hydratase (FH) deficiency is a rare familial disorder of the tricarboxylic acid cycle which is characterized by severe neurological impairment in early childhood. Several autosomal recessive mutations in the fumarate hydratase gene have been identified as a cause of the lack of fumarase activity in affected individuals. We describe a novel mutation in nucleotide 1127A>C of the fumarase cDNA which changes glutamine 376 to proline in the vicinity of the catalytic site and explains the loss of FH function. Two homozygous carriers of this mutation suffered from severe encephalopthy and died at a young age. Molecular modeling of FH structure shows that the mutation Gln376Pro in the second half of the fumarase sequence disrupts the structure of the active site. Analysis of the FH mutation and the mutant enzyme variant described here provides an explanation for the mechanism of FH deficiency at the molecular level and paves the way for the analysis of other dysfunctional FH variants.

Amino Acid Sequence↗
PubMed2004

Molecular epidemiology of childhood mitochondrial encephalomyopathies in a Finnish population: sequence analysis of entire mtDNA of 17 children reveals heteroplasmic mutations in tRNAArg, tRNAGlu, and tRNALeu(UUR) genes.

OBJECTIVES: Many heteroplasmic point mutations in tRNA genes of mitochondrial DNA (mtDNA) have been associated with human diseases. We recently reported on a prospective 7-year study in which we enrolled 116 consecutive children with undefined encephalomyopathy. Seventeen of them were found to have both a defect in the mitochondrial respiratory chain and abnormal ultrastructure of muscle mitochondria, suggesting a clinically probable mitochondrial encephalopathy. METHODS: We determined the frequency of mtDNA mutations in these 17 children by analyzing the entire sequence of mtDNA by conformation-sensitive gel electrophoresis and sequencing. RESULTS: Three heteroplasmic tRNA mutations that were considered to be pathogenic were detected. Two of the mutations were novel transitions, 10438A>G in the tRNA(Arg) gene and 14696A>G in the tRNA(Glu) gene, whereas the third one was 3243A>G, the common MELAS mutation. The mutant load was very high in the blood and skeletal muscle of the patients and markedly lower in the blood of asymptomatic maternal relatives. The 10438A>G mutation changes the nucleotide flanking the anticodon, whereas 14696A>G changes a nucleotide in the stem of the pseudouridine loop, creating a novel base pair and reducing the wobble. CONCLUSIONS: Our results emphasize that the analysis of the entire sequence of mtDNA is worthwhile in the diagnostic evaluation of patients with clinically probable mitochondrial encephalomyopathy. The frequency of pathogenic mtDNA mutations was found to be 18% among children with biochemically and histologically defined mitochondrial disease, suggesting that the likelihood of nuclear DNA mutations in such a group is several times higher than that of mtDNA mutations.

Base Sequence↗