Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Wilson disease (WD), an autosomal recessive disorder of copper transport, is characterized by impaired biliary excretion and by impaired incorporation of copper into ceruloplasmin. Toxic accumulation of copper causes tissue damage, primarily in the liver, brain, and kidneys. The gene for WD (ATP7B) has been cloned, and the protein product is predicted to be a copper-transporting P-type ATPase with high amino acid identity with that for Menkes disease, an X-linked disorder of copper transport. Mutation screening in WD patients has led to the identification of at least 40 mutations. In addition, haplotype analysis using three dinucleotide-repeat markers, D13S314, D13S301, and D13S316, has been a useful indicator of specific mutations. We have determined haplotypes for the patients and their parents and sibs, in 21 unrelated WD families from Japan. Twenty-eight different haplotypes were observed on 42 WD chromosomes. In all the patients, the ATP7B coding sequence, including the intron-exon boundaries, was screened for mutations, by SSCP, followed by direct-sequence analysis of the shifted fragments. We identified 13 mutations, of which 11 mutations are novel, including 7 mutations-1 insertion, 4 deletions, and 2 missense mutations-in the coding region. The mutations reported in previous studies are 2299insC and Arg778Leu. Two patients were shown to have the 2299insC mutation, which has occurred in many different haplotypes in several populations, indicating a mutation hot spot. Primer-extension analysis of ATP7B mRNA has revealed multiple transcription start sites. Four of the novel mutations (three 1-bp changes and one 5-bp deletion) occur in the 5' UTR and may result in altered expression of the WD gene.
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PMID:Haplotype and mutation analysis in Japanese patients with Wilson disease. 919 63

Combined methodologies of histochemistry, immunohistochemistry, sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE), reverse transcriptase polymerase chain reaction (RT-PCR) and a histochemical method specific for myofibrillar ATPase (mATPase) of the type IIX myosin heavy chain (MyHC) isoform were used to study human and rat single fibres to examine the homology between type II MyHC isoform-based fibres of both species. We demonstrate that human type II fibres exhibit antigenic mATPase and 3'-untranslated region (3'-UTR) sequence determinants homologous to the IIA and IIX but not the IIB MyHC isoforms of the rat. Both immunolabelling with anti-MyHC monoclonal antibodies and the mATPase method used with frozen sections confirmed that all human type II fibres express type IIA and/or type IIX MyHC. Quantitative immunohistochemistry failed to recognize human fibres with antigenic characteristics corresponding to hybrid IIXB MyHC-based fibres. Ca2+-stimulated maximum myosin ATPase activity, determined by quantitative histochemistry, revealed that human IIX fibres (with an optical density or OD = 0.707) display enzyme activity which is comparable to that of the rat type IIX (OD = 0.687) but lower than that of the rat type IIB fibres (OD = 0.836). The results do not support the notion that MyHC IIB is expressed in human limb muscles, even in hybrid fibres. We conclude that human type II fibres have been misclassified in numerous previous publications and that this has important implications in attempts to compare the physiological characteristics of fibre types, particularly when animal models are used.
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PMID:Comparison of the molecular, antigenic and ATPase determinants of fast myosin heavy chains in rat and human: a single-fibre study. 935 15

A general characteristic of the 3'-untranslated regions (3' UTRs) of plastid mRNAs is an inverted repeat (IR) sequence that can fold into a stem-loop structure. These stem-loops are RNA 3'-end processing signals and determinants of mRNA stability, not transcription terminators. Incubation of synthetic RNAs corresponding to the 3' UTRs of Chlamydomonas chloroplast genes atpB and petD with a chloroplast protein extract resulted in the accumulation of stable processing products. Synthetic RNAs of the petA 3' UTR and the antisense strand of atpB 3' UTR were degraded in the extract. To examine 3' UTR function in vivo, the atpB 3' UTR was replaced with the 3' UTR sequences of the Chlamydomonas chloroplast genes petD, petD plus trnR plus trnR, rbcL, petA and E. coli thrA by biolistic transformation of Chlamydomonas chloroplasts. Each 3' UTR was inserted in both the sense and antisense orientations. The accumulation of both total atpB mRNA and ATPase beta-subunit protein in all transformants was increased compared to a strain in which the atpB 3' UTR had been deleted. However, the level of discrete atpB transcripts in transformants containing the antisense 3' UTR sequences was reduced to approximately one-half that of transformants containing the 3' UTRs in the sense orientation. These results imply that both the nucleotide sequences and the stem-loop structures of the 3' UTRs are important for transcript 3'-end processing, and for accumulation of the mature mRNAs.
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PMID:The sequence and structure of the 3'-untranslated regions of chloroplast transcripts are important determinants of mRNA accumulation and stability. 948 42

The plant V-type H+-ATPase (V-ATPase) does not only serve basic housekeeping functions but is also involved in stress-induced NaCl sequestration during salinity stress. To address the question whether the same isoforms conferring housekeeping functions are equally involved in the response to high salinity, we have isolated cDNA clones for subunits A and c, as representing the peripheral V1 complex and the membrane-integral V0 complex, respectively, from the halotolerant sugar beet (Beta vulgaris L., diploid variety). RNA blot analysis with gene-specific probes revealed a coordinate expression of the cloned subunit A and c isoforms during plant development and in response to high salinity. Also, in rapidly dividing suspension-cultured cells with 10-fold increased transcript amounts as compared to young leaf tissue, the ratio of transcripts for both genes was similar to the ratio found for transcripts in leaves of different age. We have then isolated partial genomic clones (BVA/70 for Beta V-ATPase 70 kDa subunit; BVA/16-1 for Beta V-ATPase 16 kDa subunit), including the promoter regions. Transcription start mapping revealed long 5'-UTR leader sequences (230 and 172 bases, respectively) for both genes. Both promoters contain putative G-box motifs in similar distance to the TATA boxes. For a quantitative comparison of relative promoter strength, the BVA/70 and BVA/16-1 promoters linked to the luciferase reporter gene (LUC) were delivered to sugar beet suspension-cultured cells by particle bombardment. The BVA/16-1 promoter showed a 1.7-fold higher activity as compared with the BVA/70 promoter. Salt treatment induced an increase of BVA/70 (+70%) and BVA/16-1 (+57%) promoter activities, concomitant with increased transcript amounts. The following sequences have been deposited at the EMBL database X98767: Beta vulgaris V-ATPase subunit A, cDNA clone; X98851, B. vulgaris V-ATPase subunit c isoform 1, cDNA clone; Y11038, B. vulgaris V-ATPase subunit A, partial genomic clone; Y11037, B. vulgaris V-ATPase subunit c isoform 1, partial genomic clone.
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PMID:cDNA and genomic cloning of sugar beet V-type H+-ATPase subunit A and c isoforms: evidence for coordinate expression during plant development and coordinate induction in response to high salinity. 1009 75

Eukaryotic initiation factor (elF) 4A functions as a subunit of the initiation factor complex elF4F, which mediates the binding of mRNA to the ribosome. elF4A possesses ATPase and RNA helicase activities and is the prototype for a large family of putative RNA helicases (the DEAD box family). It is thought that the function of elF4A during translation initiation is to unwind the mRNA secondary structure in the 5' UTR to facilitate ribosome binding. However, the evidence to support this hypothesis is rather indirect, and it was reported that elF4A is also required for the translation of mRNAs possessing minimal 5' UTR secondary structure. Were this hypothesis correct, the requirement for elF4A should correlate with the degree of mRNA secondary structure. To test this hypothesis, the effect of a dominant-negative mutant of mammalian elF4A on translation of mRNAs with various degrees of secondary structure was studied in vitro. Here, we show that mRNAs containing stable secondary structure in the 5' untranslated region are more susceptible to inhibition by the elF4A mutant. The mutant protein also strongly inhibits translation from several picornavirus internal ribosome entry sites (IRES), although to different extents. UV crosslinking of elF4F subunits and elF4B to the mRNA cap structure is dramatically reduced by the elF4A mutant and RNA secondary structure. Finally, the elF4A mutant forms a more stable complex with elF4G, as compared to the wild-type elF4A, thus explaining the mechanism by which substoichiometric amounts of mutant elF4A inhibit translation.
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PMID:The requirement for eukaryotic initiation factor 4A (elF4A) in translation is in direct proportion to the degree of mRNA 5' secondary structure. 1133 19

Gene expression profiling was carried out comparing Con A elicited peritoneal macrophages from C57BL6 and FVBN wild-type and apolipoprotein (apo)E knockout mice. An EST, was expressed at higher levels in C57BL6 compared with FVBN mice. mapped to an atherosclerosis susceptibility locus on chromosome 19 revealed in an intercross between atherosclerosis-susceptible C57BL6 and atherosclerosis-resistant FVBN apoE knockout mice. A combination of database search and Northern analysis confirmed that corresponded to 3'-UTR of a hitherto predicted gene, named HspA12A. Blasting the National Center for Biotechnology Information database revealed a closely related homologue, HspA12B. HspA12A and -B have very close human homologues. TaqMan analysis confirmed the increased HspA12A expression (2.6-fold) in elicited peritoneal macrophages from C57BL6 compared with FVBN mice. TaqMan analysis also revealed increased HspA12A and HspA12B expression (87- and 6-fold, respectively) in lesional versus nonlesional portions of the thoracic aorta from C57BL6 apoE knockout mice on a chow diet. In situ hybridization confirmed that both genes were expressed within lesions but not within nonlesional aortic tissue. Blasting of HspA12A and HspA12B against the National Center for Biotechnology Information database (NR) revealed a hit with the Conserved Domain database for Hsp70 (pfam00012.5, Hsp70). Both genes appear to contain an atypical Hsp70 ATPase domain. The BLAST search also revealed that both genes were more similar to primitive eukaryote and prokaryote than mammalian Hsp70s, making these two genes distant members of the mammalian Hsp70 family. In summary, we describe two genes that code for a subfamily of Hsp70 proteins that may be involved in atherosclerosis susceptibility.
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PMID:Two Hsp70 family members expressed in atherosclerotic lesions. 1255 99

ATP7B is a copper-transporting P-type ATPase defective in the copper transport disorder, Wilson disease (WND). We have sequenced the 5' UTR and promoter region of ATP7B in 37 unrelated WND patients in whom partial sequencing of the coding region and intron/exon boundaries of the gene had failed to identify one or both disease-causing mutations. Three patients were found to be heterozygous for a 15 bp deletion between nucleotides -424 and -441. This deletion had been previously identified as the most common mutation in Sardinian WND patients. Two novel single-nucleotide changes were also identified within the 5' UTR and promoter of ATP7B; however, these were found at a similar frequency in control chromosomes and are apparently normal variants. These results suggest that mutations in regulatory elements of ATP7B are uncommon in patients of European ancestry, except in Sardinia.
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PMID:Genetic variation in the promoter and 5' UTR of the copper transporter, ATP7B, in patients with Wilson disease. 1461 67

Myosin light chains associate with the motor protein myosin and are believed to play a role in the regulation of its actin-based ATPase activity. Myosin light chain cDNA clones from the turkey (Meleagris gallopavo) were isolated and sequenced. One sequence corresponded to an alternative transcript, the skeletal muscle essential light chain (MYL1 isoform 1) and a second to the smooth muscle isoform of myosin light chain (MYL6). The DNA and predicted amino acid sequences of both light chain genes were compared to that of the chicken. Based on the cDNA sequence, oligonucleotide primers were designed to amplify genomic DNA from six of the seven introns of the MYL1 gene. Approximately 5 kb of DNA was sequenced (introns and 3' UTR) and evaluated for the presence of single nucleotide polymorphisms (SNPs). SNPs were verified by sequencing common intron regions from multiple individuals and three polymorphisms were used to genotype pedigreed families. MYL1 is assigned to a turkey linkage group that corresponds to a region of chicken chromosome 7 (GGA7). The results of this study provide genomic reagents for comparative studies of avian muscle components and muscle biology.
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PMID:Myosin light chain genes in the turkey (Meleagris gallopavo). 1497 Jul 26

Zellweger syndrome and its milder variants--neonatal adrenoleukodystrophy and infantile Refsum disease--comprise a clinical continuum of diseases referred to as the Zellweger spectrum. Mutations in the PEX1 gene, which consists of 24 exons and encodes a AAA ATPase protein required for peroxisomal protein import, account for approximately two-thirds of the known Zellweger spectrum patient mutations. In this paper, we report on four novel PEX1 mutations and two polymorphisms in an Australasian cohort. Two of the mutations--c.1108_1109insA and c.2391_2392delTC--that lead to the introduction of a premature termination codon in exons 5 and 14, respectively, are associated with the severe Zellweger phenotype. One patient with a milder disease phenotype was a compound heterozygote for two missense mutations (I989T and R998Q), both affecting amino acids in the second, C-terminal AAA domain of the protein. PTS1 protein import levels in cultured skin fibroblasts from this patient were almost 20% of normal control levels. We have also characterized two co-segregating polymorphisms in the 5' UTR of the PEX1 gene. Based on reporter assays, the c.-137T>C polymorphism leads to reduced PEX1 expression, whereas the c.-53C>G polymorphism leads to increased expression. When present together, these regulatory polymorphisms lead to near-normal PEX1 expression. Altered PEX1 expression due to the presence of either the c.-137T>C or the c.-53C>G variant could impact on residual PEX1 function if another co-allelic mutation was present which did not completely abolish PEX1 function. It also follows that the presence of polymorphisms in the PEX1 promoter region could have implications for patients with mutations in other PEX proteins known to interact with PEX1, such as PEX6. Thus, although not deleterious in control individuals, these polymorphisms could contribute to phenotypic heterogeneity among Zellweger spectrum patients.
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PMID:Novel PEX1 coding mutations and 5' UTR regulatory polymorphisms. 1608 92

As previously established in yeast, two sequences within mRNAs are responsible for their specific localization to the mitochondrial surface-the region coding for the mitochondrial targeting sequence and the 3'UTR. This phenomenon is conserved in human cells. Therefore, we decided to use mRNA localization as a tool to address to mitochondria, a protein that is not normally imported. For this purpose, we associated a nuclear recoded ATP6 gene with the mitochondrial targeting sequence and the 3'UTR of the nuclear SOD2 gene, which mRNA exclusively localizes to the mitochondrial surface in HeLa cells. The ATP6 gene is naturally located into the organelle and encodes a highly hydrophobic protein of the respiratory chain complex V. In this study, we demonstrated that hybrid ATP6 mRNAs, as the endogenous SOD2 mRNA, localize to the mitochondrial surface in human cells. Remarkably, fusion proteins localize to mitochondria in vivo. Indeed, ATP6 precursors synthesized in the cytoplasm were imported into mitochondria in a highly efficient way, especially when both the MTS and the 3'UTR of the SOD2 gene were associated with the re-engineered ATP6 gene. Hence, these data indicate that mRNA targeting to the mitochondrial surface represents an attractive strategy for allowing the mitochondrial import of proteins originally encoded by the mitochondrial genome without any amino acid change in the protein that could interfere with its biologic activity.
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PMID:mRNA localization to the mitochondrial surface allows the efficient translocation inside the organelle of a nuclear recoded ATP6 protein. 1675 14


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