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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
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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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    • "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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    • "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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    • "(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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