Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patients

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Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most frequent inborn error of metabolism, and accounts for 90-95% of CAH cases. The affected enzyme, P450C21, is encoded by the CYP21A2 gene, located together with a 98% nucleotide sequence identity CYP21A1P pseudogene, on...

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Autores principales:	Minutolo, C., Nadra, A.D., Fernández, C., Taboas, M., Buzzalino, N., Casali, B., Belli, S., Charreau, E.H., Alba, L., Dain, L.
Formato:	Artículo publishedVersion
Lenguaje:	Inglés
Publicado:	2011
Materias:	cytochrome P450 2C cytochrome P450 2C21 steroid 21 monooxygenase unclassified drug CYP21A2 protein, human article chromosome 6p congenital adrenal hyperplasia exon frameshift mutation gene deletion gene mutation genotype heterozygote detection human nucleotide sequence phenotype point mutation promoter region protein stability protein structure pseudogene salt wasting sequence analysis steroid 21 monooxygenase deficiency structure analysis algorithm Argentina case control study chemical structure chemistry genetic predisposition genetics mutation Mammalia Adrenal Hyperplasia, Congenital Algorithms Case-Control Studies Genetic Predisposition to Disease Humans Models, Molecular Mutation Protein Stability Steroid 21-Hydroxylase
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_19326203_v6_n1_p_Minutolo
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	paperaa:paper_19326203_v6_n1_p_Minutolo2023-06-12T16:51:28Z Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patients PLoS ONE 2011;6(1) Minutolo, C. Nadra, A.D. Fernández, C. Taboas, M. Buzzalino, N. Casali, B. Belli, S. Charreau, E.H. Alba, L. Dain, L. cytochrome P450 2C cytochrome P450 2C21 steroid 21 monooxygenase unclassified drug CYP21A2 protein, human steroid 21 monooxygenase article chromosome 6p congenital adrenal hyperplasia exon frameshift mutation gene deletion gene mutation genotype heterozygote detection human nucleotide sequence phenotype point mutation promoter region protein stability protein structure pseudogene salt wasting sequence analysis steroid 21 monooxygenase deficiency structure analysis algorithm Argentina case control study chemical structure chemistry congenital adrenal hyperplasia genetic predisposition genetics mutation Mammalia Adrenal Hyperplasia, Congenital Algorithms Argentina Case-Control Studies Genetic Predisposition to Disease Humans Models, Molecular Mutation Protein Stability Steroid 21-Hydroxylase Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most frequent inborn error of metabolism, and accounts for 90-95% of CAH cases. The affected enzyme, P450C21, is encoded by the CYP21A2 gene, located together with a 98% nucleotide sequence identity CYP21A1P pseudogene, on chromosome 6p21.3. Even though most patients carry CYP21A1P-derived mutations, an increasing number of novel and rare mutations in disease causing alleles were found in the last years. In the present work, we describe five CYP21A2 novel mutations, p.R132C, p.149C, p.M283V, p.E431K and a frameshift g.2511_2512delGG, in four non-classical and one salt wasting patients from Argentina. All novel point mutations are located in CYP21 protein residues that are conserved throughout mammalian species, and none of them were found in control individuals. The putative pathogenic mechanisms of the novel variants were analyzed in silico. A three-dimensional CYP21 structure was generated by homology modeling and the protein design algorithm FoldX was used to calculate changes in stability of CYP21A2 protein. Our analysis revealed changes in protein stability or in the surface charge of the mutant enzymes, which could be related to the clinical manifestation found in patients. © 2011 Minutolo et al. Fil:Minutolo, C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Nadra, A.D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Taboas, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Charreau, E.H. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2011 info:eu-repo/semantics/article info:ar-repo/semantics/artículo info:eu-repo/semantics/publishedVersion application/pdf eng info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_19326203_v6_n1_p_Minutolo
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
language	Inglés
orig_language_str_mv	eng
topic	cytochrome P450 2C cytochrome P450 2C21 steroid 21 monooxygenase unclassified drug CYP21A2 protein, human steroid 21 monooxygenase article chromosome 6p congenital adrenal hyperplasia exon frameshift mutation gene deletion gene mutation genotype heterozygote detection human nucleotide sequence phenotype point mutation promoter region protein stability protein structure pseudogene salt wasting sequence analysis steroid 21 monooxygenase deficiency structure analysis algorithm Argentina case control study chemical structure chemistry congenital adrenal hyperplasia genetic predisposition genetics mutation Mammalia Adrenal Hyperplasia, Congenital Algorithms Argentina Case-Control Studies Genetic Predisposition to Disease Humans Models, Molecular Mutation Protein Stability Steroid 21-Hydroxylase
spellingShingle	cytochrome P450 2C cytochrome P450 2C21 steroid 21 monooxygenase unclassified drug CYP21A2 protein, human steroid 21 monooxygenase article chromosome 6p congenital adrenal hyperplasia exon frameshift mutation gene deletion gene mutation genotype heterozygote detection human nucleotide sequence phenotype point mutation promoter region protein stability protein structure pseudogene salt wasting sequence analysis steroid 21 monooxygenase deficiency structure analysis algorithm Argentina case control study chemical structure chemistry congenital adrenal hyperplasia genetic predisposition genetics mutation Mammalia Adrenal Hyperplasia, Congenital Algorithms Argentina Case-Control Studies Genetic Predisposition to Disease Humans Models, Molecular Mutation Protein Stability Steroid 21-Hydroxylase Minutolo, C. Nadra, A.D. Fernández, C. Taboas, M. Buzzalino, N. Casali, B. Belli, S. Charreau, E.H. Alba, L. Dain, L. Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patients
topic_facet	cytochrome P450 2C cytochrome P450 2C21 steroid 21 monooxygenase unclassified drug CYP21A2 protein, human steroid 21 monooxygenase article chromosome 6p congenital adrenal hyperplasia exon frameshift mutation gene deletion gene mutation genotype heterozygote detection human nucleotide sequence phenotype point mutation promoter region protein stability protein structure pseudogene salt wasting sequence analysis steroid 21 monooxygenase deficiency structure analysis algorithm Argentina case control study chemical structure chemistry congenital adrenal hyperplasia genetic predisposition genetics mutation Mammalia Adrenal Hyperplasia, Congenital Algorithms Argentina Case-Control Studies Genetic Predisposition to Disease Humans Models, Molecular Mutation Protein Stability Steroid 21-Hydroxylase
description	Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most frequent inborn error of metabolism, and accounts for 90-95% of CAH cases. The affected enzyme, P450C21, is encoded by the CYP21A2 gene, located together with a 98% nucleotide sequence identity CYP21A1P pseudogene, on chromosome 6p21.3. Even though most patients carry CYP21A1P-derived mutations, an increasing number of novel and rare mutations in disease causing alleles were found in the last years. In the present work, we describe five CYP21A2 novel mutations, p.R132C, p.149C, p.M283V, p.E431K and a frameshift g.2511_2512delGG, in four non-classical and one salt wasting patients from Argentina. All novel point mutations are located in CYP21 protein residues that are conserved throughout mammalian species, and none of them were found in control individuals. The putative pathogenic mechanisms of the novel variants were analyzed in silico. A three-dimensional CYP21 structure was generated by homology modeling and the protein design algorithm FoldX was used to calculate changes in stability of CYP21A2 protein. Our analysis revealed changes in protein stability or in the surface charge of the mutant enzymes, which could be related to the clinical manifestation found in patients. © 2011 Minutolo et al.
format	Artículo Artículo publishedVersion
author	Minutolo, C. Nadra, A.D. Fernández, C. Taboas, M. Buzzalino, N. Casali, B. Belli, S. Charreau, E.H. Alba, L. Dain, L.
author_facet	Minutolo, C. Nadra, A.D. Fernández, C. Taboas, M. Buzzalino, N. Casali, B. Belli, S. Charreau, E.H. Alba, L. Dain, L.
author_sort	Minutolo, C.
title	Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patients
title_short	Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patients
title_full	Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patients
title_fullStr	Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patients
title_full_unstemmed	Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patients
title_sort	structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patients
publishDate	2011
url	http://hdl.handle.net/20.500.12110/paper_19326203_v6_n1_p_Minutolo
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Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patients

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