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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...

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Autores principales: Janošík, Miroslav, Sokolová, Jitka, Janošíková, Bohumila, Krijt, Jakub, Klatovská, Veronika, Kožich, Viktor
Formato: Texto
Lenguaje:English
Publicado: Mosby 2009
Materias:
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.
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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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