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Birth Prevalence of Homocystinuria in Central Europe: Frequency and Pathogenicity of Mutation c.1105C>T (p.R369C) in the Cystathionine Beta-Synthase Gene
OBJECTIVES: To estimate the frequency of the cystathionine beta-synthase deficiency caused by c.1105C>T mutation in Central Europe compared to Norway, and to examine the pathogenicity of the corresponding p.R369C mutant enzyme. STUDY DESIGN: Mutation c.1105C>T was analyzed in 600 anonymous Cze...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Mosby
2009
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653617/ https://www.ncbi.nlm.nih.gov/pubmed/18950795 http://dx.doi.org/10.1016/j.jpeds.2008.09.015 |
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author | Janošík, Miroslav Sokolová, Jitka Janošíková, Bohumila Krijt, Jakub Klatovská, Veronika Kožich, Viktor |
author_facet | Janošík, Miroslav Sokolová, Jitka Janošíková, Bohumila Krijt, Jakub Klatovská, Veronika Kožich, Viktor |
author_sort | Janošík, Miroslav |
collection | PubMed |
description | OBJECTIVES: To estimate the frequency of the cystathionine beta-synthase deficiency caused by c.1105C>T mutation in Central Europe compared to Norway, and to examine the pathogenicity of the corresponding p.R369C mutant enzyme. STUDY DESIGN: Mutation c.1105C>T was analyzed in 600 anonymous Czech newborn blood spots. Catalytic activity and quaternary structure of the p.R369C mutant was evaluated after expression in 2 cellular systems. RESULTS: Population frequency of the c.1105C>T mutation was 0.005, predicting the birth prevalence of homocystinuria of 1:40 000, which increased to 1:15 500 in a model including 10 additional mutations. In Escherichia coli the p.R369C mutant misfolded, and its activity was severely reduced, and expression in Chinese hamster ovary cells enabled proper folding with activity decreased to 63% of the wild-type enzyme. This decreased activity was not due to impaired K(m) for both substrates but resulted from V(max) lowered to 55% of the normal cystathionine beta-synthase enzyme. CONCLUSIONS: The c.1105C>T (p.R369C) allele is common also in the Czech population. Although the p.R369C mutation impairs folding and decreases velocity of the enzymatic reaction, our data are congruent with rather mild clinical phenotype in homozygotes or compound heterozygotes carrying this mutation. |
format | Text |
id | pubmed-2653617 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Mosby |
record_format | MEDLINE/PubMed |
spelling | pubmed-26536172009-03-11 Birth Prevalence of Homocystinuria in Central Europe: Frequency and Pathogenicity of Mutation c.1105C>T (p.R369C) in the Cystathionine Beta-Synthase Gene Janošík, Miroslav Sokolová, Jitka Janošíková, Bohumila Krijt, Jakub Klatovská, Veronika Kožich, Viktor J Pediatr Original Article OBJECTIVES: To estimate the frequency of the cystathionine beta-synthase deficiency caused by c.1105C>T mutation in Central Europe compared to Norway, and to examine the pathogenicity of the corresponding p.R369C mutant enzyme. STUDY DESIGN: Mutation c.1105C>T was analyzed in 600 anonymous Czech newborn blood spots. Catalytic activity and quaternary structure of the p.R369C mutant was evaluated after expression in 2 cellular systems. RESULTS: Population frequency of the c.1105C>T mutation was 0.005, predicting the birth prevalence of homocystinuria of 1:40 000, which increased to 1:15 500 in a model including 10 additional mutations. In Escherichia coli the p.R369C mutant misfolded, and its activity was severely reduced, and expression in Chinese hamster ovary cells enabled proper folding with activity decreased to 63% of the wild-type enzyme. This decreased activity was not due to impaired K(m) for both substrates but resulted from V(max) lowered to 55% of the normal cystathionine beta-synthase enzyme. CONCLUSIONS: The c.1105C>T (p.R369C) allele is common also in the Czech population. Although the p.R369C mutation impairs folding and decreases velocity of the enzymatic reaction, our data are congruent with rather mild clinical phenotype in homozygotes or compound heterozygotes carrying this mutation. Mosby 2009-03 /pmc/articles/PMC2653617/ /pubmed/18950795 http://dx.doi.org/10.1016/j.jpeds.2008.09.015 Text en © 2009 Mosby, Inc. https://creativecommons.org/licenses/by/3.0/ Open Access under CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/) license |
spellingShingle | Original Article Janošík, Miroslav Sokolová, Jitka Janošíková, Bohumila Krijt, Jakub Klatovská, Veronika Kožich, Viktor Birth Prevalence of Homocystinuria in Central Europe: Frequency and Pathogenicity of Mutation c.1105C>T (p.R369C) in the Cystathionine Beta-Synthase Gene |
title | Birth Prevalence of Homocystinuria in Central Europe: Frequency and Pathogenicity of Mutation c.1105C>T (p.R369C) in the Cystathionine Beta-Synthase Gene |
title_full | Birth Prevalence of Homocystinuria in Central Europe: Frequency and Pathogenicity of Mutation c.1105C>T (p.R369C) in the Cystathionine Beta-Synthase Gene |
title_fullStr | Birth Prevalence of Homocystinuria in Central Europe: Frequency and Pathogenicity of Mutation c.1105C>T (p.R369C) in the Cystathionine Beta-Synthase Gene |
title_full_unstemmed | Birth Prevalence of Homocystinuria in Central Europe: Frequency and Pathogenicity of Mutation c.1105C>T (p.R369C) in the Cystathionine Beta-Synthase Gene |
title_short | Birth Prevalence of Homocystinuria in Central Europe: Frequency and Pathogenicity of Mutation c.1105C>T (p.R369C) in the Cystathionine Beta-Synthase Gene |
title_sort | birth prevalence of homocystinuria in central europe: frequency and pathogenicity of mutation c.1105c>t (p.r369c) in the cystathionine beta-synthase gene |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653617/ https://www.ncbi.nlm.nih.gov/pubmed/18950795 http://dx.doi.org/10.1016/j.jpeds.2008.09.015 |
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