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At least 127 records · Page 7Linked to original sources
PubMed1990

Chromosomal localization of the human alpha-L-iduronidase gene (IDUA) to 4p16.3.

The lysosomal hydrolase alpha-L-iduronidase (IDUA) is one of the enzymes in the metabolic pathway responsible for the degradation of the glycosaminoglycans heparan sulfate and dermatan sulfate. In humans a deficiency of IDUA leads to the accumulation of glycosaminoglycans, resulting in the lysosomal storage disorder mucopolysaccharidosis type I. A genomic subclone and a cDNA clone encoding human IDUA were used to localize IDUA to chromosome 4p16.3 by in situ hybridization and this was confirmed by Southern blot analysis. This localization is different from that of a previous report mapping IDUA to chromosome 22 and places the gene for IDUA in the same region of chromosome 4 as the Huntington disease gene. Measurement of expressed human IDUA activity in human-mouse hybrid cell lines confirmed that IDUA is on chromosome 4.

Animals↗
PubMed1984

Human alpha-L-iduronidase. II. Comparative biochemical and immunologic properties of the purified low and high uptake forms.

The physicokinetic and immunologic properties of the purified low and high uptake forms of the human lysosomal hydrolase, alpha-L-iduronidase, have been determined and compared. The apparent Km and Vmax values for the low and high uptake forms were similar toward two artificial substrates, 4-methylumbelliferyl-alpha-L-iduronide (0.07 and 0.06 mmol/l; 16.15 and 14.85 mumol/min/mg, respectively), and phenyl-alpha-L-iduronide (1.42 and 1.66 mmol/l; 0.83 and 1.05 mumol/min/mg, respectively), and one natural substrate, anhydro-[3H]-mannitol-iduronide (0.86 and 1.04 mmol/l; 2.50 and 2.79 mumol/min/mg, respectively). The pH optima for both purified forms also were similar for each of the three substrates ( approximately 3.50, approximately 3.50, and approximately 4.50, respectively). Heparin markedly inhibited the 4-methylumbelliferyl-alpha-L-iduronide activities of both the low and high uptake forms, while dermatan sulfate and heparan sulfate were more inhibitory toward the low uptake activity. EDTA was a potent inhibitor of both enzyme forms; the divalent cations, Mg2+ and Ca2+, could recover up to 30% of the enzymatic activities after EDTA treatment. p-Chloromercuribenzoate and maleate also were inhibitory, whereas dithiothreitol and 2-mercaptoethanol were stimulatory. Both enzyme forms had similar thermostabilities ; the half-lives at 45, 52, and 60 degrees C were about 38, 24 and 12 min, respectively. The low and high uptake forms were immunologically cross-reactive as demonstrated by Ouchterlony double immunodiffusion and immunotitration studies using anti-human low uptake antibodies.

Endocytosis↗
PubMed1994

Evidence for degradation of mRNA encoding alpha-L-iduronidase in Hurler fibroblasts with premature termination alleles.

Mutations in the gene encoding alpha-L-iduronidase (IDUA) are the cause of Hurler syndrome. Fibroblasts from patients homozygous for nonsense IDUA alleles have much reduced mRNA detectable by Northern analysis, as has been observed in many other instances of premature translation termination. Yet RT-PCR (reverse transcription followed by PCR amplification) showed a normal level of a segment covering exons 1 and 2 in Hurler cells homozygous for alleles bearing the nonsense mutations, Q70X or W402X. The 3' end of the segment was between exons 2 and 4. The results indicate that the nonsense RNA was degraded to fragment(s), independent of the position of the mutation (exon 2 or exon 9, respectively). Treatment of the cells with cycloheximide resulted in some increase of intact mRNA, suggesting that translation is required for mRNA degradation.

Alleles↗
PubMed1993

Identification of mutations in the alpha-L-iduronidase gene (IDUA) that cause Hurler and Scheie syndromes.

Mucopolysaccharidosis type I (MPS-I) is an autosomal recessive genetic disease caused by a deficiency of the lysosomal glycosidase alpha-L-iduronidase. Hurler (severe), Scheie (mild), and Hurler/Scheie (intermediate) syndromes are clinical subtypes of MPS-I, but it is difficult to distinguish between these subtypes by biochemical measurements. Mutation analysis was undertaken to provide a molecular explanation for the clinical variation seen in MPS-I. Using chemical cleavage and direct PCR sequencing, we have defined four previously undescribed mutations for MPS-I (delG1702, 1060 + 2t-->c, R89Q, and 678-7g-->a). R89Q and 678-7g-->a were found to be present in 40% of Scheie syndrome alleles. Expression of R89Q demonstrated reduced stability and activity of the mutant protein. The deleterious effect of R89Q may be potentiated by a polymorphism (A361T) to produce an intermediate phenotype. 678-7g-->a was found to be a mild mutation, since it was present in an index Scheie syndrome patient in combination with a severe allele (W402X). This mutation appears to allow a very small amount of normal mRNA to be produced from the allele which is likely to be responsible for the mild clinical phenotype observed. Both the 5' and 3' splice site mutations (1060 + 2t-->c and 678-7g-->a, respectively) result in high proportions of mature mRNAs containing introns, which has not been observed for other splicing mutations. The frameshift mutation (delG1702) and the 5' splice site mutation (1060 + 2t-->c) are both thought to be associated with severe MPS-I. The identification of these MPS-I mutations begins to document the expected genetic heterogeneity in MPS-I and provides the first molecular explanations for the broad range of clinical phenotypes observed.

Animals↗
PubMed1998

Human alpha-L-iduronidase (IDUA) gene: correlation of polymorphic DNA haplotype and IDUA activity in Chinese population.

The correlation of polymorphic DNA haplotype of the alpha-L-iduronidase (IDUA) gene and IDUA activity in Chinese subjects was investigated. Genomic DNA extracted from 85 randomly sampled normal individuals was used to amplify fragments containing the polymorphic change site A8, Q33H (exon 1), R105Q (exon 3), A361T (exon 8), or V454I (exon 9). The PCR amplified products were analyzed by means of restriction fragment length polymorphism (RFLP) or allele specific oligonucleotide (ASO) hybridization. Leukocytes were isolated from the above 85 samples, and their IDUA activities were determined. A wide range of IDUA activity (50-300 nmol/h/mg cell protein) with an average of 156 nmol/h/mg cell protein was observed. When the allele frequency was compared between individuals with IDUA activity below 90% or above 110% of the average, a bias toward the common allele "1" of Q33H (Gln33) was detected in individuals with higher IDUA activity. Conversely, the polymorphic allele "2" of R105Q (Gln105), A361T (Thr361), and V454I (Ile454) was found in the higher IDUA activity group. Linkage disequilibrium analysis of the haplotype data revealed strong nonrandom association among the polymorphic alleles of R105Q, A361T, and V454I. Of the haplotypes constructed by Q33H, R105Q, A361T, and V454I, a positive correlation between haplotype 1,2,2,2 (Gln33, Gln105, Thr361, Ile454) and IDUA activity was observed. The IDUA activity was found to increase with Gln105, Thr361, or Ile454 polymorphic changes by mutagenesis and expression of IDUA cDNA in COS-7 cells. By combining the positive effect of Gln105, Thr361, and Ile454 in one cDNA construct, it may be possible to produce a high activity IDUA protein for MPS I enzyme replacement therapy.

Alleles↗
PubMed1998

Human alpha-L-iduronidase (IDUA) gene: apparent recombination in intron 2 by haplotype analysis in a Taiwanese population.

The polymorphic DNA haplotype of the alpha-L-iduronidase (IDUA) gene in a Taiwanese population was investigated. Genomic DNA extracted from 85 volunteers was used to amplify fragments containing the polymorphic sites A8, A20 and Q33H from exon 1 and a variable number of tandem repeats (VNTR) region in intron 2. Additionally, sites R105Q and L118 in exon 3, A314 from exon 7, A361T and T388 from exon 8, T410 and V454I from exon 9, and R489 from exon 10 were amplified. The polymerase chain reaction-amplified products were analyzed by restriction fragment length polymorphism (RFLP) analysis, allele specific oligonucleotide (ASO) hybridization, or gel electrophoresis. Of the examined polymorphisms, the intron 2 VNTR was not in Hardy-Weinberg equilibrium. Conversely, all 11 single base change polymorphisms were in Handy-Weinberg equilibrium. Linkage disequilibrium analysis of the haplotype data revealed strong nonrandom association between A8 and A20 in exon 1 as well as among R105Q, A314, A361T, T388, T410, V454I, and R489 in exons 3 to 10. In contrast, little linkage disequilibrium between two clusters of linked polymorphisms on either side of the VNTR was observed. The results suggest apparent recombination in intron 2 of the IDUA gene, with little or no recombination in exon 1 or exons 3 to 10.

Adult↗
PubMed2004

From D-glucose to biologically potent L-hexose derivatives: synthesis of alpha-L-iduronidase fluorogenic detector and the disaccharide moieties of bleomycin A2 and heparan sulfate.

A novel and convenient route for the synthesis of biologically potent and rare L-hexose derivatives from D-glucose is described. Conversion of diacetone-alpha-D-glucose (14) into 1,2:3,5-di-O-isopropylidene-beta-L-idofuranose (19) was efficiently carried out in two steps. Orthogonal isopropylidene rearrangement of compound 19 led to 1,2:5,6-di-O-isopropylidene-beta-L-idofuranose (27), which underwent regioselective epimerization at the C3 position to give the L-talo- and 3-functionalized L-idofuranosyl derivatives. Hydrolysis of compound 19 under acidic conditions furnished 1,6-anhydro-beta-L-idopyranose (35) in excellent yield, which was successfully transformed into the corresponding L-allo, L-altro, L-gulo, and L-ido derivatives via regioselective benzylation, benzoylation, triflation and nucleophilic substitution as the key steps. Applications of these 1,6-anhydro-beta-L-hexopyranoses as valuable building blocks to the syntheses of 4-methylcoumarin-7-yl-alpha-L-iduronic acid and the disaccharide moieties of bleomycin A(2) as well as heparan sulfate are highlighted.

Bleomycin↗