Is the MPS I Medical Phenotype Associated with Specific Causative Factors? (original) (raw)
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IDUA mutational profile and genotype-phenotype correlations in mucopolysaccharidosis type I
Molecular Genetics and Metabolism, 2016
Mucopolysaccharidosis Type I is a lysosomal storage disorder with varying degrees of phenotypic severity caused by mutations in IDUA. Over 200 disease-causing variants in IDUA have been reported. We describe the profile of disease-causing variants in 291 individuals with Mucopolysaccharidosis Type I for whom IDUA sequencing was performed, focussing on the UK subset of the cohort. A total of 63 variants were identified, of which 20 were novel, and the functional significance of the novel variants is explored. The severe form of Mucopolysaccharidosis Type I is treated with haematopoietic stem cell transplantation, known to have improved outcomes with earlier age at treatment. Developing genotypephenotype relationships would therefore have considerable clinical utility, especially in the light of the development of newborn screening programs for Mucopolysaccharidosis Type I. Associations between genotype and phenotype are examined in this cohort, particularly in the context of the profile of variants identified in UK individuals. Relevant associations can be made for the majority of UK individuals based on the presence of nonsense or truncating variants as well as other associations described in this report.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2003
Mucopolysaccharidosis type I (MPS I; McKusick 25280; Hurler syndrome, Hurler -Scheie syndrome and Scheie syndrome) is caused by a deficiency in the lysosomal hydrolase, a-L-iduronidase (EC 3.2.1.76). MPS I patients present within a clinical spectrum bounded by the extremes of Hurler and Scheie syndromes. The a-L-iduronidase missense mutations R89Q and R89W were investigated and altered an important arginine residue proposed to be a nucleophile activator in the catalytic mechanism of a-L-iduronidase. The R89Q a-L-iduronidase mutation was shown to result in a reduced level of a-L-iduronidase protein ( V 10% of normal control) compared to a normal control level of a-L-iduronidase protein that was detected for the R89W a-L-iduronidase mutation. When taking into account a-L-iduronidase specific activity, the R89W mutation had a greater effect on a-L-iduronidase activity than the R89Q mutation. However, overall the R89W mutation produced more residual a-L-iduronidase activity than the R89Q mutation. This was consistent with MPS I patients, with an R89W allele, having a less severe clinical presentation compared to MPS I patients with either a double or single allelic R89Q mutation. The effects of the R89Q and R89W mutations on enzyme activity supported the proposed role of R89 as a nucleophile activator in the catalytic mechanism of a-L-iduronidase. Crown
Human Molecular Genetics, 1994
A group of 46 European patients with mucopolysaccharidosis type I (MPS I) was screened for mutations of the a-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.
Identification and characterization of 13 new mutations in mucopolysaccharidosis type I patients
Molecular Genetics and Metabolism, 2003
In this study we have investigated a group of 29 Brazilian patients, who had been diagnosed with the lysosomal storage disorder, Mucopolysaccharidosis type I (MPS-I). MPS I is caused by a deficiency in the lysosomal hydrolase, a-L L -iduronidase. Ninety percent of the MPS I patients in this study were genotyped and revealed 10 recurrent and thirteen novel IDUA gene mutations. Eight of these new mutations and three common mutations W402X, P533R, and R383H were individually expressed in CHO-K1 cells and analyzed for a-L L -iduronidase protein and enzyme activity. A correlation was observed between the MPS I patient clinical phenotype and the associated mutant a-L L -iduronidase protein/enzyme activity expressed in CHO-K1 cells. This was the first time that Brazilian MPS I patients had been thoroughly analyzed and highlighted the difficulties of mutation screening and clinical phenotype assessment in populations with high numbers of unique mutations. Ó 2002 Published by Elsevier Science (USA).
Human Mutation, 2011
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.
Mucopolysaccharidosis type I - Clinical and genetic characteristics of Romanian patients
2020
Background: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by a deficiency of α-L-iduronidase (IDUA), which leads to the accumulation of partially digested glycosaminoglycans (dermatan sulfate and heparan sulfate) in the lysosomes and induces multisystemic alteration. Hurler (severe), Scheie (mild), and Hurler/Scheie (intermediate) syndromes are clinical subtypes of MPS-I. To date, more than 290 IDUA mutations have been reported. The purpose of this study was to present the clinical and genetic characteristics of Romanian MPS I syndrome patients and their genotype-phenotype correlation. Patients and methods: Seven patients (5 girls and 2 boys) with MPS type I, belonging to 4 unrelated families, aged 0,75-17.9 years, were enrolled. The study methods consisted in: clinical and standard auxological assessment, bone radiographs, joint ultrasonography, goniometry, neurological and psychological evaluation, hepatic and splenic ultrasonogra...
Molecular Genetics and Metabolism Reports, 2014
Mucopolysaccharidosis type I (MPSI) is a rare autosomal recessive disorder caused by mutations in the gene encoding the lysosomal enzyme α-L-iduronidase (IDUA), which is instrumental in the hydrolysis of the glycosaminoglycans, dermatan and heparan sulfate. The accumulation of unhydrolyzed glycosaminoglycans leads to pathogenesis in multiple tissue types, especially those of skeletal, nervous, respiratory, cardiovascular, and gastrointestinal origin. Although molecular diagnostic tools for MPSI have been available since the identification and characterization of the IDUA gene in 1992, Colombia, Ecuador, and Peru have lacked such methodologies. Therefore, the mutational profile of the IDUA gene in these countries has largely been unknown. The goal of this study was to characterize genotypes in 14 patients with MPSI from Colombia, Ecuador, and Peru. The most common mutation found at a frequency of 42.8% was W402X. Six patients presented with seven novel mutations, a high novel mutational rate in this population (32%). These novel mutations were validated using bioinformatic techniques. A model of the IDUA protein resulting from three of the novel missense mutations (Y625C, P385L, R621L) revealed that these mutations alter accessible surface area values, thereby reducing the accessibility of the enzyme to its substrates.
Diagnostic Pathology, 2011
Background: 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. Results: 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.
Human Mutation, 2001
Mucopolysaccharidosis type II (MPS2, or Hunter syndrome), rare X-linked lysosomal storage disorder, results from deleterious mutations in the iduronate-2-sulfatase (IDS) gene. We report here the mutational analysis of a total of 40 unrelated Italian MPS II patients ranging from mild to severe phenotype. We are able to assign the genotype to 29 of them (72.5%), identifying 22 different mutations, five of which are unpublished (c.533delTT, W12X, N265I, c.1131-1142del, c.1131-1305del). A total of 55.2% of the molecularly characterised patients resulted from missense mutations, 20.7% from nonsense mutations, and another 13.8% of patients from small deletions (<20pb) or splice mutations, whereas 10.3% of the cases carried major structural alterations such as large deletion and rearrangements. The results reported here support the evidence of the mutational heterogeneity of the IDS gene as well as the difficulty to correlate genotype and phenotype in the patients with MPSII. However, the molecular characterisation of the patients is advantageous, making the carrier detection feasible for the females in the family at risk and improving the reliability of prenatal diagnosis techniques. Moreover, it provides a good foundation for therapeutic strategies.