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)

alpha-L-Iduronidase (IDUA) has been intensively studied due to its causative role in mucopolysaccharidosis type I (Hurler, Scheie and Hurler/Scheie syndromes). The recent cloning of a human IDUA cDNA has resulted in a reevaluation of the chromosomal location of this gene. Previously assigned to chromosome 22, IDUA now has been localized to 4p16.3, the region of chromosome 4 associated with Huntington's disease (HD). The existence of a battery of cloned DNA, physical map information, and genetic polymorphism data for this region has allowed the rapid fine mapping of IDUA within the terminal cytogenetic band of 4p. IDUA was found to be coincident with D4S111, an anonymous locus displaying a highly informative multiallele DNA polymorphism. This map location, 1.1 X 10(6) bp from the telomere, makes IDUA the most distal cloned gene assigned to 4p. However, it falls within a segment of 4p16.3 that has been eliminated from the HD candidate region, excluding a role for IDUA in this disorder.
Somat Cell Mol Genet 1991 Jul
PMID:Huntington disease-linked locus D4S111 exposed as the alpha-L-iduronidase gene. 183 39

A group of 46 European patients with mucopolysaccharidosis type I (MPS I) was screened for mutations of the alpha-L-iduronidase gene. The 2 common nonsense mutations, W402X and Q70X, were identified in, respectively, 37% and 35% of mutant alleles. Considerable differences were seen in the frequency of these 2 mutations in patients from North Europe (Norway and Finland) and other European countries (mainly The Netherlands and Germany). In Scandinavia, W402X and Q70X account for 17% and 62% of the MPS I alleles, respectively, while in other European countries W402X is about 2.5 times more frequent (48%) than Q70X (19%). Eight novel mutations are described including 4 missense mutations, 1 nonsense mutation, 1 insertion of 2 base pairs, and 2 deletions of 1 and 12 base pairs.
Hum Mol Genet 1994 Jun
PMID:Mucopolysaccharidosis type I: identification of 8 novel mutations and determination of the frequency of the two common alpha-L-iduronidase mutations (W402X and Q70X) among European patients. 795 Dec 28

Enzyme replacement is a potential therapy for mucopolysaccharidosis I (MPS I), a lysosomal storage disorder caused by alpha-L-iduronidase deficiency. Previous work showed improvement in the tissues of MPS I dogs treated intravenously for 3 months with recombinant human alpha-L-iduronidase (25,000 units or approximately 0.1 mg/kg/week). We have now treated an MPS I-affected dog for 13 months to assess the clinical effects of enzyme replacement. The treated dog gained more weight, was more active, and had less joint stiffness than the untreated littermate. Biochemical and histologic studies demonstrated uptake of alpha-L-iduronidase and decreased lysosomal storage in the liver, kidney, spleen, lymph nodes, synovium, adrenals, and lungs. The brain had detectable enzyme activity and decreased glycosaminoglycan storage although histologic improvement was not evident. Cartilage and heart valve did not show any detectable improvement. A fivefold higher dose (approximately 0.5 mg/kg) administered five times over 10 days to two other dogs resulted in higher tissue enzyme activity and similarly decreased glycosaminoglycan storage and excretion. Antibodies to human alpha-L-iduronidase were induced in all treated dogs and may be associated with immune complex deposition and proteinuria. Recombinant canine alpha-L-iduronidase also induced antibody formation to a similar degree. The results support the conclusion that enzyme replacement is a promising therapy for MPS I though immunologic complications may occur.
Biochem Mol Med 1996 Aug
PMID:Long-term and high-dose trials of enzyme replacement therapy in the canine model of mucopolysaccharidosis I. 881 35

Mucopolysaccharidosis type I (MPS I) is considered to represent the prototypical mucopolysaccharide storage disorder. Although a spectrum of severity is seen within the MPS I subgroup, Hurler syndrome represents the most severe and frequent manifestation of MPS I. We describe here the generation of a murine model for Hurler syndrome by targeted disruption of the murine Idua gene. Homozygous Idua -/- mice have no detectable alpha-L-iduronidase enzyme activity and show increased urinary glycosaminoglycan levels. Although normal appearing at birth, Idua -/- mice develop a flattened facial profile and thickening of the digits discernible by 3 weeks of age. No obvious growth deficiency nor mortality is seen within the first 20 weeks of life. Radiographs reveal anterior flaring of the ribs and thickening of the facial bones as early as 4 weeks of age with more extensive dysostosis detectable by 15 weeks of age. At 4 weeks of age, lysosomal storage is noted primarily within reticuloendothelial cells with abundant lysosomes noted in Kupffer cells, splenic sinusoidal lining cells, and glial cells. More widespread lysosomal storage is noted by 8 weeks of age in hepatocytes, chondrocytes, neurons, as well as renal tubular cells. Thus, targeted disruption of the murine Idua locus has produced a murine strain representative of the severe form of MPS I. This model should permit detailed evaluation of the pathophysiology of lysosomal storage disorders and provide a small animal model for the testing and development of enzyme replacement and gene therapy regimes.
Hum Mol Genet 1997 Apr
PMID:Murine mucopolysaccharidosis type I: targeted disruption of the murine alpha-L-iduronidase gene. 909 52

Mucopolysaccharidosis type I (MPS-I) is an autosomal recessive lysosomal storage disorder resulting from a deficiency of the lysosomal protein alpha-l-iduronidase (IDUA). Patients present within a broad spectrum of phenotypes from severe (Hurler syndrome) to clinically less severe (Scheie syndrome). Since 1982 a special program for the diagnosis and prevention of lysosomal storage diseases has operated in the former Soviet Union (FSU). We report the genotypes of 25 MPS-I patients with different clinical severities from the FSU. All the patients were screened for two common mutations (W402X and Q70X) and four other mutations (P533R, R89Q, A327P, 474 2a-->g). W402X and Q70X alleles accounted for 4 and 44%, respectively. Using SSCP analysis and subsequent direct sequencing we also detected four novel mutations (P533L, Q63X, Y343X, and A75P) in the IDUA gene, together with two mutations (974ins12bp, 134del12bp) described elsewhere. All were found in the heterozygous form in MPS-I patients with different clinical severities. A total of 32 mutant alleles leading to MPS-I was identified with nine patients fully genotyped. Four patients were homozygous for Q70X while five others were genetic compounds. Besides the eight identified mutations, six known polymorphisms were found. The spectrum of mutant alleles discovered is highly specific and proves the peculiarity of genetic loads in the FSU. Our data suggest a closer relationship between the FSU and Scandinavian populations than with Western and Central European populations.
Mol Genet Metab 1998 Oct
PMID:Molecular genetics of mucopolysaccharidosis type I: mutation analysis among the patients of the former Soviet Union. 978 9

Mucopolysaccharidosis Type I (MPS I) is the lysosomal storage disease caused by the deficient activity of alpha-L-iduronidase (IDUA). In man, MPS I can occur in severe, mild, or intermediate forms known as the Hurler, Scheie, or Hurler/Scheie syndromes, respectively. MPS I also has been described in cats, dogs, and mice. This manuscript reports the identification and characterization of the mutation causing MPS I in cats. To obtain wild-type feline IDUA cDNAs, two PCR-based strategies were used. PCR primers were constructed from a conserved region of the published human and dog sequences and used to amplify a 224-bp IDUA fragment from normal cat genomic DNA. This fragment was then used to screen a feline uterus cDNA library. PCR also was used to directly amplify IDUA fragments from the same cDNA library. Two overlapping feline IDUA cDNAs encoding 466 amino acid residues of the feline IDUA polypeptide ( approximately 85% of the mature protein based on comparison to the human, dog, and mouse sequences) were obtained by these strategies. To identify the mutation causing MPS I in cats, DNA sequencing was carried out on the corresponding IDUA region from several affected animals. A 3-bp deletion was found on both IDUA alleles in each of the MPS I animals, predicting the deletion of a single aspartate residue from the feline IDUA polypeptide. To confirm the authenticity of this mutation, heteroduplex, SSCP, and transient expression studies were carried out. Over 100 animals from the MPS I colony were screened for the presence of the mutation by heteroduplex and SSCP analyses-in all cases the presence of the 3-bp deletion was 100% concordant with the disease phenotype. For transient expression studies, the two partial, overlapping feline cDNAs were combined and joined in-frame to the 5' end of the canine IDUA cDNA. This wild-type, hybrid cDNA expressed IDUA activity up to sixfold over endogenous levels after transfection into COS-1 cells. A modified full-length IDUA cDNA containing the 3-bp deletion did not express IDUA activity in a transient expression system, providing proof that this lesion was the cause of feline MPS I.
Mol Genet Metab 1999 Jun
PMID:Identification and characterization of the molecular lesion causing mucopolysaccharidosis type I in cats. 1035 9

Enzyme replacement therapy (ERT) has been developed and trialed for the treatment of human lysosomal storage disorder patients. The viability of ERT for the treatment of these severe multiple pathology disorders has subsequently been established. However, in both animal model studies and human clinical trials, some individuals have been shown to develop an immune response to the replacement protein. This potential complication for treatment has been investigated by the infusion of recombinant human alpha-L-iduronidase (rh-alpha-L-iduronidase) into nonimmune and immunized rats to simulate mucopolysaccharidosis type I ERT in the presence of different levels of antibody. In rats with high antibody titers to rh-alpha-L-iduronidase (titer 1,024,000) there was evidence of altered organ distribution and subcellular targeting when compared to either lower titer immunized rats (titers less than 64,000) or nonimmune rats (titers 512-1024). In addition, hypersensitivity reactions were observed for high titer rats (titer 1,024,000) during rh-alpha-L-iduronidase infusion, but not for the other two treatment groups. A rat with an antibody titer of 64,000 had only minor changes in subcellular targeting and organ distribution when infused with rh-alpha-L-iduronidase. This implied that a high level of antibody was required to effect changes in alpha-L-iduronidase enzyme targeting and distribution. Notably, in the high titer rats, the antibody produced appeared to increase the tissue and subcellular level of rh-alpha-L-iduronidase specific activity. This suggested that antibody production may not always result in an adverse effect on ERT.
Mol Genet Metab 2000 Apr
PMID:Enzyme replacement therapy in mucopolysaccharidosis I: altered distribution and targeting of alpha-L-iduronidase in immunized rats. 1087 Aug 45

Enzyme replacement therapy (ERT) has long been considered an approach to treating lysosomal storage disorders caused by deficiency of lysosomal enzymes. ERT is currently used to treat Gaucher disease and is being developed for several lysosomal storage disorders now that recombinant sources of the enzymes have become available. We have continued development of ERT for mucopolysaccharidosis I (MPS I) using the feline model. Recombinant alpha-L-iduronidase was administered intravenously at low dose (approximately 0.1 mg/kg or 25,000 units/kg) to four cats and high dose (0.5 mg/kg or 125,000 units/kg) to two cats on a weekly basis for 3- or 6-month terms. Clinical examinations showed distinct clearing of corneal clouding in one cat although clinical effects in the others were not evident. Biochemical studies of the cats showed that the enzyme was distributed to a variety of tissues although the liver and spleen contained the highest enzyme activities. Glycosaminoglycan storage was decreased in liver and spleen, and the histologic appearance improved in liver, spleen, and renal cortex. Enzyme was not consistently detected in cerebral cortex, brainstem, or cerebellum and the histologic appearance and ganglioside profiles did not improve. A variety of other tissues showed low variable uptake of enzyme and no distinct improvement. IgG antibodies to alpha-L-iduronidase were observed in five cats with higher titers noted when higher doses were administered. Mild complement activation occurred in three cats. Enzyme replacement therapy was effective in reversing storage in some tissues at the biochemical and histologic level in MPS I cats but an improved tissue distribution and prevention of a significant immune response could make the therapy more effective.
Mol Genet Metab 2001 Mar
PMID:Enzyme replacement therapy in feline mucopolysaccharidosis I. 1124 25

Recent studies have suggested that the use of aminoglycosides to suppress disease-causing nonsense mutations may be a promising new therapy for a large number of genetic diseases. However, gentamicin is currently the only clinically relevant aminoglycoside shown to suppress premature stop mutations in a mammalian system. We compared the ability of the clinically approved aminoglycosides gentamicin, tobramycin, and amikacin to suppress premature stop mutations. Using readthrough reporter constructs as well as mammalian cDNAs containing naturally occurring premature stop mutations, we found that each of these aminoglycosides can suppress many premature stop mutations in a context-dependent manner in a mammalian translation system. Our results indicate that the tetranucleotide termination signal (the stop codon and the nucleotide 3' of the stop codon) is the primary determinant for aminoglycoside-mediated suppression. The levels of termination suppression achieved by tobramycin were substantially lower than those observed with gentamicin. In contrast, amikacin stimulated suppression in a manner that was generally similar to gentamicin. Amikacin produced higher levels of readthrough than gentamicin at some contexts, demonstrating a unique pattern of context dependence. Experiments with mammalian cDNAs confirmed these results and demonstrated that these aminoglycosides can also suppress disease-associated premature stop mutations previously identified in the IDUA gene (responsible for the lysosomal storage disease mucopolysaccharidosis I) and the P53 gene (associated with many forms of cancer). Taken together, these results suggest that amikacin represents an alternative to gentamicin for suppression therapy in certain contexts, thus providing a means of optimizing the efficacy of aminoglycoside-mediated suppression of premature stop mutations.
J Mol Med (Berl) 2002 Jun
PMID:Clinically relevant aminoglycosides can suppress disease-associated premature stop mutations in the IDUA and P53 cDNAs in a mammalian translation system. 1207 12

Immune response to replacement therapy has been reported for a range of therapeutic strategies being developed for the treatment of patients with genetic disease. The potential problem of immune response to enzyme replacement therapy has been investigated in alpha-L-iduronidase immunized rats, representing a model of the lysosomal storage disorder Hurler syndrome (alpha-L-iduronidase deficiency). The antibody response to alpha-L-iduronidase showed that the positional location of antibody reactivity was similar for different immunized rats, but the precise linear sequence epitopes identified, varied between rats. A monoclonal antibody reacting to an epitope in close proximity to one high antigenicity site on alpha-L-iduronidase was used to reproduce the in vivo effect of altered enzyme tissue distribution, previously observed in immunized rats infused with alpha-L-iduronidase. The study demonstrated that during an immune response, antibody reacting to a single epitope could partially control the tissue distribution of antigen from circulation.
Mol Genet Metab
PMID:Immune response to enzyme replacement therapy: single epitope control of antigen distribution from circulation. 1235 40


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