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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
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 glycosami...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121354/ https://www.ncbi.nlm.nih.gov/pubmed/27896125 http://dx.doi.org/10.1016/j.ymgmr.2014.10.001 |
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author | Pineda, Tatiana Marie, Sulie Gonzalez, Janneth García, Ana L. Acosta, Amparo Morales, Manuel Correa, Luz N. Vivas, Ricardo Escobar, Xiomara Protzel, Ana Barba, Maria Ospina, Sandra Corredor, Clara Mansilla, Sandra Velasco, Harvy M. |
author_facet | Pineda, Tatiana Marie, Sulie Gonzalez, Janneth García, Ana L. Acosta, Amparo Morales, Manuel Correa, Luz N. Vivas, Ricardo Escobar, Xiomara Protzel, Ana Barba, Maria Ospina, Sandra Corredor, Clara Mansilla, Sandra Velasco, Harvy M. |
author_sort | Pineda, Tatiana |
collection | PubMed |
description | 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. 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. |
format | Online Article Text |
id | pubmed-5121354 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-51213542016-11-28 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 Marie, Sulie Gonzalez, Janneth García, Ana L. Acosta, Amparo Morales, Manuel Correa, Luz N. Vivas, Ricardo Escobar, Xiomara Protzel, Ana Barba, Maria Ospina, Sandra Corredor, Clara Mansilla, Sandra Velasco, Harvy M. Mol Genet Metab Rep The Lysosome 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. 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. Elsevier 2014-10-30 /pmc/articles/PMC5121354/ /pubmed/27896125 http://dx.doi.org/10.1016/j.ymgmr.2014.10.001 Text en © 2014 The Authors http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). |
spellingShingle | The Lysosome Pineda, Tatiana Marie, Sulie Gonzalez, Janneth García, Ana L. Acosta, Amparo Morales, Manuel Correa, Luz N. Vivas, Ricardo Escobar, Xiomara Protzel, Ana Barba, Maria Ospina, Sandra Corredor, Clara Mansilla, Sandra Velasco, Harvy M. Genotypic and bioinformatic evaluation of the alpha-l-iduronidase gene and protein in patients with mucopolysaccharidosis type I from Colombia, Ecuador and Peru |
title | Genotypic and bioinformatic evaluation of the alpha-l-iduronidase gene and protein in patients with mucopolysaccharidosis type I from Colombia, Ecuador and Peru |
title_full | Genotypic and bioinformatic evaluation of the alpha-l-iduronidase gene and protein in patients with mucopolysaccharidosis type I from Colombia, Ecuador and Peru |
title_fullStr | Genotypic and bioinformatic evaluation of the alpha-l-iduronidase gene and protein in patients with mucopolysaccharidosis type I from Colombia, Ecuador and Peru |
title_full_unstemmed | Genotypic and bioinformatic evaluation of the alpha-l-iduronidase gene and protein in patients with mucopolysaccharidosis type I from Colombia, Ecuador and Peru |
title_short | Genotypic and bioinformatic evaluation of the alpha-l-iduronidase gene and protein in patients with mucopolysaccharidosis type I from Colombia, Ecuador and Peru |
title_sort | genotypic and bioinformatic evaluation of the alpha-l-iduronidase gene and protein in patients with mucopolysaccharidosis type i from colombia, ecuador and peru |
topic | The Lysosome |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121354/ https://www.ncbi.nlm.nih.gov/pubmed/27896125 http://dx.doi.org/10.1016/j.ymgmr.2014.10.001 |
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