Mucopolysaccharidosis type I in 21 Czech and Slovak patients: Mutation analysis suggests a functional importance of C‐terminus of the IDUA protein
Open Access
- 24 April 2009
- journal article
- Published by Wiley in American Journal of Medical Genetics Part A
- Vol. 149A (5), 965-974
- https://doi.org/10.1002/ajmg.a.32812
Abstract
Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder that is caused by a deficiency of the enzyme α‐L‐iduronidase (IDUA). Of the 21 Czech and Slovak patients who have been diagnosed with MPS I in the last 30 years, 16 have a severe clinical presentation (Hurler syndrome), 2 less severe manifestations (Scheie syndrome), and 3 an intermediate severity (Hurler/Scheie phenotype). Mutation analysis was performed in 20 MPS I patients and 39 mutant alleles were identified. There was a high prevalence of the null mutations p.W402X (12 alleles) and p.Q70X (7 alleles) in this cohort. Four of the 13 different mutations were novel: p.V620F (3 alleles), p.W626X (1 allele), c.1727 + 2T > G (1 allele) and c.1918_1927del (2 alleles). The pathogenicity of the novel mutations was verified by transient expression studies in Chinese hamster ovary cells. Seven haplotypes were observed in the patient alleles using 13 intragenic polymorphisms. One of the two haplotypes associated with the mutation p.Q70X was not found in any of the controls. Haplotype analysis showed, that mutations p.Q70X, p.V620F, and p.D315Y probably have more than one ancestor. Missense mutations localized predominantly in the hydrophobic core of the enzyme are associated with the severe phenotype, whereas missense mutations localized to the surface of the enzyme are usually associated with the attenuated phenotypes. Mutations in the 130 C‐terminal amino acids lead to clinical manifestations, which indicates a functional importance of the C‐terminus of the IDUA protein.Keywords
This publication has 42 references indexed in Scilit:
- Outcomes of hematopoietic stem cell transplantation for Hurler's syndrome in Europe: a risk factor analysis for graft failureBone Marrow Transplantation, 2007
- UCSF Chimera?A visualization system for exploratory research and analysisJournal of Computational Chemistry, 2004
- Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human α-L-iduronidase (laronidase)The Journal of Pediatrics, 2004
- α-l-Iduronidase Premature Stop Codons and Potential Read-Through in Mucopolysaccharidosis Type I PatientsJournal of Molecular Biology, 2004
- The Jalview Java alignment editorBioinformatics, 2004
- Mutational analysis of 85 mucopolysaccharidosis type I families: frequency of known mutations, identification of 17 novel mutations and in vitro expression of missense mutationsHuman Genetics, 2001
- Bone marrow transplantation for mucopolysaccharidosis type I: experience of two British centresArchives of Disease in Childhood, 1997
- Multiple polymorphisms within the α-L-iduronidase gene (IDUA): implications for a role in modification of MPS-I disease phenotypeHuman Molecular Genetics, 1993
- Prenatal diagnosis of Hurler disease by analysis of α‐iduronidase in chorionic villiJournal of Inherited Metabolic Disease, 1991
- Single-Step Method of RNA Isolation by Acid Guanidinium Thiocyanate–Phenol–Chloroform ExtractionAnalytical Biochemistry, 1987