+ Site Statistics
References:
52,572,879
Abstracts:
28,705,754
PMIDs:
27,750,366
DOIs:
25,464,004
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Identification and molecular characterization of alpha-L-iduronidase mutations present in mucopolysaccharidosis type I patients undergoing enzyme replacement therapy



Identification and molecular characterization of alpha-L-iduronidase mutations present in mucopolysaccharidosis type I patients undergoing enzyme replacement therapy



Human Mutation 24(3): 199-207



Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by a deficiency of alpha-L-iduronidase (IDUA). Mutations in the gene are responsible for the enzyme deficiency, which leads to the intralysosomal storage of the partially degraded glycosaminoglyeans dermatan sulfate and heparan sulfate. Molecular characterization of MPS I patients has resulted in the identification of over 70 distinct mutations in the IDUA gene. The high degree of molecular heterogeneity reflects the wide clinical variability observed in MPS I patients. Six novel mutations, c.1087C>T (p.R363C), c.1804T>A (p.F6021), c.793G>C, c.712T>A (p.L238Q), c.1727+2T>A, and c.1269C>G (p.S423R), in a total of 14 different mutations, and 13 different polymorphic changes, including the novel c. 246C>G (p.H82Q), were identified in a cohort of 10 MPS I patients enrolled in a clinical trial of enzyme-replacement therapy. Five novel amino acid substitutions and c.236C>T (p.A79V) were engineered into the wild-type IDUA cDNA and expressed. A p.G265R readthrough mutation, arising from the c-793G>C splice mutation, was also expressed. Each mutation reduced IDUA protein and activity levels to varying degrees with the processing of many of the mutant forms also affected by IDUA. The varied properties of the expressed mutant forms of IDUA reflect the broad range of biochemical and clinical phenotypes of the 10 patients in this study. IDUA kinetic data derived from each patient's cultured fibroblasts, in combination with genotype data, was used to predict disease severity. Finally, residual IDUA protein concentration in cultured fibroblasts showed a weak correlation to the degree of immune response to enzyme,replacement therapy in each patient. Copyright 2004 Wiley-Liss, Inc.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 012169211

Download citation: RISBibTeXText

PMID: 15300847

DOI: 10.1002/humu.20081


Related references

Mucopolysaccharidosis type I: identification of alpha-L-iduronidase mutations in Tunisian families FT La mucopolysaccharidose de type 1: identification des mutations du gene alpha-L-iduronidase dans des familles tunisiennes. 2007

Mucopolysaccharidosis type I: Identification and characterization of mutations affecting alpha-L-iduronidase activity. Journal of the Formosan Medical Association 101(6): 425-428, 2002

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. Human Molecular Genetics 3(6): 861-866, 1994

Mucopolysaccharidosis type I: molecular characteristics of two novel alpha-L-iduronidase mutations in Tunisian patients. Diagnostic Pathology 6: 47, 2011

Mutational analysis of the alpha-L-iduronidase gene in 10 unrelated Korean type I mucopolysaccharidosis patients: Identification of four novel mutations. Clinical Genetics 66(6): 575-576, 2004

Alpha-L-iduronidase and enzyme replacement therapy for mucopolysaccharidosis I. Expert Opinion on Biological Therapy 2(8): 967-976, 2003

Enzyme replacement therapy in patients who have mucopolysaccharidosis I and are younger than 5 years: results of a multinational study of recombinant human alpha-L-iduronidase (laronidase). Pediatrics 120(1): E37-E46, 2007

Mucopolysaccharidosis type I: identification of 13 novel mutations of the alpha-L-iduronidase gene. Human Mutation 6(1): 91-94, 1995

Mucopolysaccharidosis type I: identification of alpha-L-iduronidase mutations in Tunisian families. Archives de Pediatrie 14(10): 1183-1189, 2007

Mucopolysaccharidosis type I: characterization of novel mutations affecting alpha-L-iduronidase activity. Clinical Genetics 56(1): 66-70, 1999

Enzyme replacement therapy in mucopolysaccharidosis I: altered distribution and targeting of alpha-L-iduronidase in immunized rats. Molecular Genetics and Metabolism 69(4): 277-285, 2000

Mucopolysaccharidosis type I: identification of 8 novel mutations and determination of the frequency of the two common -L-iduronidase mutations (W402X and Q70X) among European patients. Human Molecular Genetics 3(6): 861-866, 1994

Recombinant alpha-L-iduronidase: characterization of the purified enzyme and correction of mucopolysaccharidosis type I fibroblasts. Biochemical Journal 304: 43-49, 1994

N-glycan structures and downstream mannose-phosphorylation of plant recombinant human alpha-L-iduronidase: toward development of enzyme replacement therapy for mucopolysaccharidosis I. Plant Molecular Biology 95(6): 593-606, 2017

Mutational analysis of mucopolysaccharidosis type VI patients undergoing a trial of enzyme replacement therapy. Human Mutation 23(3): 229-233, 2004