Disease relevance of IDUA

• A deficiency of IDUA in humans leads to the accumulation of these glycosaminoglycans and results in the lysosomal storage disorder mucopolysaccharidosis type I. We have isolated and sequenced cDNA clones containing part of the human IDUA coding region and used PCR from reverse-transcribed RNA to obtain the full IDUA sequence [1].
• Molecular analysis of Hurler syndrome in Druze and Muslim Arab patients in Israel: multiple allelic mutations of the IDUA gene in a small geographic area [2].
• Mucopolysaccharidosis type I (i.e., Hurler, Hurler-Scheie, and Scheie syndromes) and type II (i.e., Hunter syndrome) are lysosomal storage disorders resulting from alpha-L-iduronidase (IDUA) deficiency and iduronate-2-sulfatase (IDS) deficiency, respectively [3].
• We have previously shown in a murine model the therapeutic potential of lentiviral IDUA vector-mediated gene therapy, in which human IDUA cDNA was driven by the cytomegalovirus promoter [4].
• Two retroviral vectors containing a full-length human IDUA cDNA were constructed using Moloney murine leukemia virus (MoMLV)-based vector backbones [5].

Psychiatry related information on IDUA

• Previously assigned to chromosome 22, IDUA now has been localized to 4p16.3, the region of chromosome 4 associated with Huntington's disease (HD) [6].
• Q70X is one of the frequent diseases causing mutations of alpha-L-iduronidase (IDUA), leading to a severe phenotype with mental retardation and various somatic abnormalities, and making a request for PGD is understandable [7].

High impact information on IDUA

• We report on the mapping of a gene causing ACH/HCH to human chromosome 4p16.3, by linkage to the iduronidase A (IDUA) locus, in 15 informative families (Z max = 3.01 at theta = 0 for ACH; Z max = 4.71 at theta = 0 for ACH/HCH) [8].
• A positive lod score of z = 3.35 with no recombinants was obtained with an intragenic marker for IDUA [9].
• Our results reveal Mps1 as a critical regulator of chromosome number in zebrafish, and demonstrate how slight genetic perturbation of a mitotic checkpoint factor can dramatically reduce the fidelity of chromosome segregation during vertebrate meiosis [10].
• These data are consistent with a model that predicts that the MPS-1-dependent phosphorylation of KVS-1 sustains cell excitability by controlling K+ flux [11].
• Electrophysiological analysis in Chinese hamster ovary (CHO) cells demonstrates that MPS-1 activity leads to a significant decrease in the macroscopic current [11].

Chemical compound and disease context of IDUA

• Hurler syndrome (mucopolysaccharidosis IH or MPS IH) is a congenital mucopolysaccharide storage disorder resulting from a genetic deficiency of alpha-L-iduronidase (IDUA), which is required for lysosomal degradation of glycosaminoglycans heparan sulfate and dermatan sulfate [5].
• We found that a Hurler syndrome fibroblast cell line heterozygous for the IDUA stop mutations Q70X and W402X showed a significant increase in alpha-L-iduronidase activity when cultured in the presence of gentamicin, resulting in the restoration of 2.8% of normal alpha-L-iduronidase activity [12].
• Mucopolysaccharidosis type I (MPS I, Hurler and Scheie syndromes) is an autosomal recessive lysosomal storage disorder that results from a deficiency of the hydrolase alpha-L-iduronidase (IDUA) which is involved in the lysosomal degradation of both heparan sulphate (HS) and dermatan sulphate (DS) [13].
• Effective therapeutic strategies for mucopolysaccharidosis type I (MPSI) rely on mannose-6-phosphate receptor-mediated uptake of extracellular alpha-l-iduronidase (IDUA), the missing lysosomal enzyme in this disease, by deficient cells [14].
• Hepatobiliary imaging with the various technetium-labeled IDA compounds is more than 90% sensitive and specific for the diagnosis of acute cholecystitis [15].

Biological context of IDUA

• Notably, a new IDUA mutation A300T was also identified in the proband, his sister, and his mother, accounting for reduced IDUA activity in these individuals; the asymptomatic sister, whose cells demonstrated normal glycosaminoglycan metabolism, is thus a compound heterozygote for W402X and the new allele [3].
• Measurement of expressed human IDUA activity in human-mouse hybrid cell lines confirmed that IDUA is on chromosome 4 [16].
• Multiple techniques, including automated sequencing of the entire IDS and IDUA coding regions, were employed to unravel the molecular genetic basis of these intriguing observations [3].
• The two-mutation allele was identified in a family from Gaza; the other three alleles were found in seven families, five of them Druze, residing in a very small area of northern Israel. Since such clustering suggests a classic founder effect, the presence of three mutant alleles of the IDUA gene was unexpected [2].
• Multiple polymorphisms within the alpha-L-iduronidase gene (IDUA): implications for a role in modification of MPS-I disease phenotype [17].

Anatomical context of IDUA

• Northern blot analysis with IDUA cDNA detected only a single 2.3-kilobase mRNA species in human placental RNA; however, PCR analysis of fibroblast, liver, kidney, and placental RNA showed the existence of alternatively spliced mRNA from the IDUA gene [1].
• However, since cloning of the IDUA gene, mutation analysis has provided some molecular explanations for the range of MPS-I phenotypes, in turn facilitating the selection and evaluation of patients undergoing experimental treatment protocols such as bone marrow transplantation [18].
• These mutations lead to a deficiency of the glycosidase alpha-L-iduronidase (IDUA), which is required for the degradation of heparan sulphate and dermatan sulphate and thus the storage of these glycosaminoglycans in the lysosome [18].
• Eight- to 10-week-old mice were injected via the tail vein with a lentiviral vector expressing human IDUA cDNA driven by the albumin gene promoter selectively expressed in hepatocytes [4].
• In transfected COS-7 cells, R619G caused significant reduction in enzyme activity (1.5% of normal activity), although it did not cause significant reduction in IDUA mRNA or protein level [19].

Associations of IDUA with chemical compounds

• 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 [16].
• Enzyme produced by the progeny of the transduced human CD34+ cells carrying IDUA cDNA corrected Hurler fibroblasts via mannose-6-phosphate receptors [5].
• In an attempt to avoid maturation of the N-linked glycans of IDUA, the same IDUA transgene was introduced into the Arabidopsis cgl background, which is deficient in the activity of N-acetylglucosaminyl transferase I (EC 2.4.1.101), the first enzyme in the pathway of complex glycan biosynthesis [20].
• IDUA protein was easily detected on Western blots of extracts from the T(2) seeds, and extracts contained IDUA activity as high as 2.9 nmol 4-methylumbelliferone (4 MU)/min/mg total soluble protein (TSP), corresponding to approximately 0.06 microg IDUA/mg TSP [20].
• In this study we investigated whether the aminoglycoside gentamicin can suppress stop mutations within the IDUA gene [12].

Other interactions of IDUA

• 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 [16].
• To optimize a gene transfer system for hematopoietic stem cell gene therapy of patients with mucopolysaccharidosis (MPS) type I, 10 retroviral vectors were constructed to express the human alpha-L-iduronidase (IDUA) cDNA [21].

Analytical, diagnostic and therapeutic context of IDUA

• 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 [16].
• One month after treatment, IDUA activity was present in the liver and spleen of treated mice; an expression level of 1% normal IDUA activity was sufficient to reduce the GAG level in liver, spleen, kidney, heart, and lung [4].
• The expression of IDUA in the organs of i.v.- and i.p.-treated mice was also analysed by real-time reverse-transcription (RT) PCR and compared by relative quantification [22].
• Thyroid enlargement, as assessed by palpation, was found in 59 of 268 children (22%) in the IDA group and in 165 of 2693 (6.1%) subjects in the control area (chi 2 = 88; P < 0.0001) [23].
• EXPERIMENTAL DESIGN: The expression pattern of MPS-1 was determined in primary gastric cancer specimens and gastric cancer cell lines via immunohistochemistry and Western blotting [24].

References