Mucopolysaccharidosis type I: Identification of 8 novel mutations and frequency of the common α-L-iduronidase mutations (W402X and Q70X) among European patients

Erasmus Universiteit Rotterdam, Rotterdam, South Holland, Netherlands
Human Molecular Genetics (Impact Factor: 6.39). 07/1994; 3(6):861-6. DOI: 10.1093/hmg/3.6.861
Source: PubMed


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.

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    • "This novel framshift (Leu530fs) in exon 11 changed codon 530 for leucine (CTG) to a premature termination codon (TGA), 30 amino acids downstream from the termination codon of the enzyme glycopeptide. In addition to these mutations, eighteen previously identified and one novel polymorphisms were identified in the Tunisian MPS I alleles (Table 2) [2,7,11,12]. "
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    ABSTRACT: Mucopolysaccharidosis type I (MPS I) is an autosomal storage disease resulting from defective activity of the enzyme α-L-iduronidase (IDUA). This glycosidase is involved in the degradation of heparan sulfate and dermatan sulfate. MPS I has severe and milder phenotypic subtypes.Aim of study: This study was carried out on six newly collected MPS I patients recruited from many regions of Tunisia.Patients and methods: Mutational analysis of the IDUA gene in unrelated MPS I families was performed by sequencing the exons and intron-exon junctions of IDUA gene. Two novel IDUA mutations, p.L530fs (1587_1588 insGC) in exon 11 and p.F177S in exon 5 and two previously reported mutations p.P533R and p.Y581X were detected. The patient in family 1 who has the Hurler phenotype was homozygous for the previously described nonsense mutation p.Y581X.The patient in family 2 who also has the Hurler phenotype was homozygous for the novel missense mutation p.F177S. The three patients in families 3, 5 and 6 were homozygous for the p.P533R mutation. The patient in family 4 was homozygous for the novel small insertion 1587_1588 insGC. In addition, eighteen known and one unknown IDUA polymorphisms were identified. The identification of these mutations should facilitate prenatal diagnosis and counseling for MPS I in Tunisia.
    Full-text · Article · Jun 2011 · Diagnostic Pathology
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    • "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; Scott et al., 1992; 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. "
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    ABSTRACT: Mutational analysis of the IDUA gene was performed in a cohort of 102 European patients with mucopolysaccharidosis type I. A total of 54 distinct mutant IDUA alleles were identified, 34 of which were novel including 12 missense mutations, 2 nonsense mutations, 12 splicing mutations, 5 micro-deletions, 1 micro-duplication 1 translational initiation site mutation, and 1 'no-stop' change (p.X654RextX62). Evidence for the pathological significance of all novel mutations identified was sought by means of a range of methodological approaches, including the assessment of evolutionary conservation, RT-PCR/in vitro splicing analysis, MutPred analysis and visual inspection of the 3D-model of the IDUA protein. Taken together, these data not only demonstrate the remarkable mutational heterogeneity characterizing type 1 mucopolysaccharidosis but also illustrate our increasing ability to make deductions pertaining to the genotype-phenotype relationship in disorders manifesting a high degree of allelic heterogeneity.
    Full-text · Article · Jun 2011 · Human Mutation
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    • "A large number of polymorphisms and non-pathogenic sequence variants have been described in the IDUA gene [23,22,24]. The effect of these sequence variants on the IDUA activity has not been clearly defined, especially when they are associated with specific mutations. "
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    ABSTRACT: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by a genetic defect in alpha-L-iduronidase (IDUA) which is involved in the degradation of dermatan and heparan sulfates. The disease has severe and milder phenotypic subtypes. The aim of this study was the detection of mutations in the IDUA gene from 12 additional MPS I patients with various clinical phenotypes (severe, 8 cases; intermediate, 3 cases; mild, 1 case). In this study, the IDUA mutations in eight unrelated Tunisian families were performed by amplifying and sequencing the IDUA exons and intron-exon jonctions. Five IDUA mutations were detected: one is the L578Q, a novel mutation found, in milder patient. The others were the previously described: P533R, Y581X, F602X and R628X that produce a severe and intermediate phenotype. In addition, eighteen variants, including eight previously unreported polymorphisms (IVS6+21c>a, IVS7+79c>t, IVS7-45 g>c, IVS9+36t>c, IVS10+140c>a, IVS11+33c>t, IVS12+13c>t and IVS12-31c>g), were detected. This paper, showed a heterogeneous pattern of mutations and polymorphisms among Tunisian patients.
    Full-text · Article · Apr 2011 · Diagnostic Pathology
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