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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 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.

SUBMITTER: Vazna A

PROVIDER: S-EPMC3526155 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Mucopolysaccharidosis type I in 21 Czech and Slovak patients: mutation analysis suggests a functional importance of C-terminus of the IDUA protein.

Vazna Alzbeta A Beesley Clare C Berna Linda L Stolnaja Larisa L Myskova Helena H Bouckova Michaela M Vlaskova Hana H Poupetova Helena H Zeman Jiri J Magner Martin M Hlavata Anna A Winchester Bryan B Hrebicek Martin M Dvorakova Lenka L

American journal of medical genetics. Part A 20090501 5

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 ...[more]

PMID: 19396826

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Project description:BackgroundProviding hospital care is an essential objective of national health policies. The countries that share common history, when they emerged from the same health system and similar conditions in the early 1990s, after the division of Czechoslovakia, became the objects of evaluation of the development of technical efficiency of hospital care. The subsequent development of their health care system also was very similar, but no longer entirely identical. The article aims to identify the trends and disparities in the productivity of the capacities of hospital care on the regional level (NUTS III.) in the Czech Republic and the Slovak Republic in 2009-2018 before the COVID-19 pandemic using the multi-criteria decision methods.MethodsThe window analysis as a dynamic DEA method based on moving averages and also the Malmquist Index, that allows the evaluation of changes in relative efficiency and of changes in the production possibilities frontier have become the key methods for evaluating the over time efficiency evolution. To model technical efficiency, an output-oriented method assuming constant returns to scale was chosen. Aggregated input and output parameters for each region were the object of study.ResultsThe results showed that differences in the efficiency trends in terms of the examined parameters among the individual regions are slightly greater in the Czech Republic than in the Slovak Republic. The least efficient regions are those where capital cities are located. Furthermore, the analysis showed that in 2018 all of the Slovak Republic regions improved its productivity compared to 2009 and that technological conditions had a significant impact on this improvement. The results of the Czech Republic regions show productivity improvement in 57% of the regions that, on the contrary, was due to changes in technical efficiency.ConclusionsIt should be recommended to the state- and regional-level governments to refrain from unilaterally preferring the orientation of public policies on the efficiency of the provision of hospital care, and rather focus on increasing the quality and availability of hospital care, especially in smaller, rural, and border regions, in the interest of population safety during pandemics and other emergencies.

Project description:BACKGROUND:The mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease resulting from the defective activity of the enzyme ?-L-iduronidase (IDUA). The disease has three major clinical subtypes (severe Hurler syndrome, intermediate Hurler-Scheie syndrome and attenuated Scheie syndrome). We aim to identify the genetic variants in MPS I patients and to investigate the effect of the novel splice site mutation on splicing of IDUA- mRNA variability using bioinformatics tools. METHODS:The IDUA mutations were determined in four MPS I patients from four families from Northern Tunisia, by amplifying and sequencing each of the IDUA exons and intron-exon junctions. RESULTS:One novel splice site IDUA mutation, c.1650?+?1G?>?T in intron 11 and two previously reported mutations, p.A75T and p.R555H, were detected. The patients in families 1 and 2 who have the Hurler phenotype were homozygotes for the novel splice site mutation c.1650?+?1G?>?T. The patient in family 3, who also had the Hurler phenotype, was a compound heterozygote for the novel splice site mutation c.1650?+?1G?>?T and for the previously reported missense mutation p.A75T. The patient in family 4 who had the Hurler-Scheie phenotype was a compound heterozygote for the novel splice site mutation c.1650?+?1G?>?T and for the previously reported missense mutation p.R555H. In addition, four known IDUA polymorphisms were identified. Bioinformatics tools allowed us to associate the variant c.1650?+?1G?>?T with the severe clinical phenotype of MPS I. This variant affects the essential nucleotide +?1 (G to T) of the donor splice site of IDUA intron 11. The G?>?T in intron 11 leads to wild type donor site broken with minus 19.97% value compared to normal value with 0%, hence the new splice site acceptor has plus 5.59%. CONCLUSIONS:The present findings indicate that the identified mutations facilitate the accurate carrier detection (genetic counseling of at-risk relatives) and the molecular prenatal diagnosis in Tunisia.

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Mucopolysaccharidosis type I in 21 Czech and Slovak patients: mutation analysis suggests a functional importance of C-terminus of the IDUA protein.

Publications

Mucopolysaccharidosis type I in 21 Czech and Slovak patients: mutation analysis suggests a functional importance of C-terminus of the IDUA protein.

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