title: Mucopolysaccharidosis type I in 21 Czech and Slovak patients: mutation analysis suggests a functional importance of C-terminus of the IDUA protein.
abstract: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder that is caused by a deficiency of the enzyme alpha-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.
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine and General Teaching Hospital, Charles University in Prague, Prague, Czech Republic.
authors.forename: Alzbeta
authors.initials: A
authors.lastname: Vazna
authors.forename: Clare
authors.initials: C
authors.lastname: Beesley
authors.forename: Linda
authors.initials: L
authors.lastname: Berna
authors.forename: Larisa
authors.initials: L
authors.lastname: Stolnaja
authors.forename: Helena
authors.initials: H
authors.lastname: Myskova
authors.forename: Michaela
authors.initials: M
authors.lastname: Bouckova
authors.forename: Hana
authors.initials: H
authors.lastname: Vlaskova
authors.forename: Helena
authors.initials: H
authors.lastname: Poupetova
authors.forename: Jiri
authors.initials: J
authors.lastname: Zeman
authors.forename: Martin
authors.initials: M
authors.lastname: Magner
authors.forename: Anna
authors.initials: A
authors.lastname: Hlavata
authors.forename: Bryan
authors.initials: B
authors.lastname: Winchester
authors.forename: Martin
authors.initials: M
authors.lastname: Hrebicek
authors.forename: Lenka
authors.initials: L
authors.lastname: Dvorakova
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D020134:Catalytic Domain / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007068:Iduronidase / Q000235:genetics*; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D008059:Mucopolysaccharidosis I / Q000235:genetics*; D009154:Mutation; D017434:Protein Structure, Tertiary / Q000235:genetics
chemical_list: D007068:Iduronidase