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 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. © 2009 Wiley-Liss, Inc.

IDUA mutational profiling of a cohort of 102 European patients with mucopolysaccharidosis type I: identification and characterization of 35 novel α-L-iduronidase (IDUA) alleles

“…The remaining amino acid replacements (p.G84R, p.Y76C, p.T103P, p.E276K, p.N348K, p.L396P and p.A436P) affected solvent accessible residues. Consistent with previous findings [Rempel et al, 2005;Vazna et al, 2009;Sugawara et al, 2008], those mutations that occur in the protein core (including the predicted active site), were associated with the severe (H) form of MPS I, whereas the missense mutations which affected surface-located residues were associated with the more attenuated clinical phenotypes (H/S, S) ( Figure 2 and Supp. Table S5).…”

“…Among the analyzed group, 25 patients were either homozygous or compound heterozygous for the two common deleterious nonsense mutations (p.Q70X and p.W402X); their severe clinical phenotype concurred with those of 91 previously reported patients with comparable genotypes [Bunge et al, 1994;Gort et al, 1998;Hein et al, 2003;Li et al, 2002;Matte et al, 2003;Vazna et al, 2009;Venturi et al, 2002;Voskoboeva et al 1998]. In agreement with previously reported genotype-phenotype correlations, a severe phenotype was not only associated with the p.W402X mutation in compound heterozygosity with both c.1650+5G>A and p.A327P [Bunge et al, 1994;Venturi et al, 2002;Vazna et al, 2009] but also with homozygosity for p.A327P and p.G51D [Gatti et al, 1997]. Also consistent with previous data [Beesley et al, 2001;Tieu et al, 1995 ], homozygosity for p.L490P and compound heterozygosity for p.Q70X and c.1333_1335del3 yielded mild phenotypes in two other patients (Supp .…”

Worldwide distribution of common IDUA pathogenic variants

“…As can be seen in Figure 1 and Table 1, p.Trp402Ter is by far the most common pathogenic variant underlying MPS I. It is the major allele in the United States (45%), 23,24 Mexico (29%), 25 Colombia (50%), 26 Brazil (29%), [27][28][29] the United Kingdom (45%), 30 the Netherlands (42%), 31,32 Germany (50%), 31,32 the Czech Republic and Slovakia (33%), 33 Spain (62%) 31,34,35 and Australia (34%), 36 that is, in Europe and countries colonized mainly by Europeans.…”

Early treatment is associated with improved cognition in Hurler syndrome

“…Figure 2 presents the developmental trajectories of all FIGURE 1: Average developmental trajectories grouped by age at transplantation. Developmental trajectories for (A) cognitive skills, (B) adaptive behavior, (C) receptive language, and (D) expressive language are shown for children who underwent umbilical cord blood transplantation at 4 months (blue), 12 months (yellow), and 26 months (red) of age, which are the median ages at transplantation for each of the patient groups (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), and 18 months, respectively). To account for the relationship between baseline cognitive skills and age, cognitive ratios were set at the medians for each group, which were 0.87, 0.92, and 0.70, respectively.…”