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Genotypic and bioinformatic evaluation of the alpha-l-iduronidase gene and protein in patients with mucopolysaccharidosis type I from Colombia, Ecuador and Peru.

ABSTRACT: Mucopolysaccharidosis type I (MPSI) is a rare autosomal recessive disorder caused by mutations in the gene encoding the lysosomal enzyme ?-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. This is the first characterization of the mutational profile of the IDUA gene in patients with MPSI in Colombia, Ecuador, and Peru. The findings contribute to our understanding of IDUA gene expression and IDUA enzyme function, and may help facilitate early and improved diagnosis and management for patients with MPSI.

SUBMITTER: Pineda T

PROVIDER: S-EPMC5121354 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Genotypic and bioinformatic evaluation of the alpha-l-iduronidase gene and protein in patients with mucopolysaccharidosis type I from Colombia, Ecuador and Peru.

Pineda Tatiana T Marie Sulie S Gonzalez Janneth J García Ana L AL Acosta Amparo A Morales Manuel M Correa Luz N LN Vivas Ricardo R Escobar Xiomara X Protzel Ana A Barba Maria M Ospina Sandra S Corredor Clara C Mansilla Sandra S Velasco Harvy M HM

Molecular genetics and metabolism reports 20141030

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 ...[more]

PMID: 27896125

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Project description:BackgroundFour Andean countries of Bolivia, Colombia, Ecuador, and Peru introduced national health-focused conditional cash transfer (CCT) programs in the 2000s. This study probes whether policymakers in these countries targeted CCT programs to subregions with the highest prevalence of ill-health or those with the lowest socioeconomic status (SES) to evaluate the equity of geographic targeting and means-testing, as well as the potential role of normative frames, bounded rationality, and clientelism as explanatory mechanisms for inequities in social spending.MethodsThe distribution of vaccination coverage, underweight, stunting, and child deaths is established both within and between subnational regions and SES quintiles from 1998 to 2012 using every available nationally representative household survey. The equity of CCT program targeting and strength of association with subregional SES and health outcomes are measured using generalized entropy index decomposition and meta-regression. Finally, simple predictive models for CCT targeting are created using lagged subregional SES, health outcomes, and concentration indices.ResultsBolivia and Peru both effectively targeted at-risk subregions, but subregions in Peru with no CCT program coverage result in higher mistargeting rates for the country as a whole. Only Bolivia failed to attain CCT coverage concentration indices that are at least as large as the health inequalities they are targeting. Despite this insufficient progressivity, Bolivia has the most efficient subregional targeting, while the lowest rates of mistargeting for child deaths are found in Colombia and Ecuador. Finally, the simple predictive model performs as well or better than observed CCT coverage distribution for every country, year, and outcome.ConclusionsBoth Peru and Ecuador have targeted programs to their poorest populations effectively, demonstrating that this is possible with both universal and geographic targeting. No clear evidence of clientelism was found, while the dominant normative frame underlying CCT program targeting decisions appears to be the relative SES of subregions, rather than absolute SES, prevalence of health outcomes, or health inequalities. To reduce the inequitable impacts of bounded rationality, policymakers can use simple predictive models to target CCT coverage effectively and without leaving behind the most vulnerable populations that happen to live in more affluent subregions.

Dataset Information

Genotypic and bioinformatic evaluation of the alpha-l-iduronidase gene and protein in patients with mucopolysaccharidosis type I from Colombia, Ecuador and Peru.

Publications

Genotypic and bioinformatic evaluation of the alpha-l-iduronidase gene and protein in patients with mucopolysaccharidosis type I from Colombia, Ecuador and Peru.

Similar Datasets

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