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

Erasmus Universiteit Rotterdam, Rotterdam, South Holland, Netherlands
Human Molecular Genetics (Impact Factor: 6.68). 07/1994; 3(6):861-6. DOI: 10.1093/hmg/3.6.861
Source: PubMed

ABSTRACT 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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Available from: C. Phillip Morris, Aug 22, 2015
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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.
    Human Mutation 06/2011; 32(6):E2189-210. DOI:10.1002/humu.21479 · 5.05 Impact Factor
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    • "Despite the high degree of molecular heterogeneity, some mutations show a higher prevalence in certain geographic locations. Among Caucasian patients, two mutant alleles, p.W402X and p.Q70X, are prevalent [Bunge et al., 1994, 1995; Gort et al., 1998], while p.P533R is frequent in Mediterranean patients [Alif et al., 1999; Chkioua et al., 2007]. The mutations p.W402X and p.Q70X are regularly associated with the most severe phenotype and apparently have the highest genotype–phenotype correlation. "
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    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.
    American Journal of Medical Genetics Part A 05/2009; 149A(5):965-74. DOI:10.1002/ajmg.a.32812 · 2.05 Impact Factor
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    • "(i) The severe form of MPS type I is known as Hurler's disease or MPS I-H. In a study of European patients, the two common nonsense mutations, W402X and Q70X, were identified in 37% and 35% of mutant alleles respectively (Bunge et al, 1994). These alleles are not found in patients with the milder phenotypes of MPS I. Their presence in a patient being considered for allogeneic BMT would be useful in confirming phenotypic severity as milder phenotypes are not considered for BMT. "
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    ABSTRACT: Lysosomal storage disorders (LSDs) are genetic defects caused by lysosomal hydrolase deficiencies. These deficiencies lead to substrate accumulation affecting cells, tissues and organs. Detecting abnormal compound excretion and deficient enzymes assist diagnosis of these disorders for treatment and prevention. This mini review summarizes clinical presentations and diagnostic workup of LSDs and updates the new development in the area.
    Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 03/2006; 38(1):100-2.
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