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

Autores
Minutolo, C.; Nadra, A.D.; Fernández, C.; Taboas, M.; Buzzalino, N.; Casali, B.; Belli, S.; Charreau, E.H.; Alba, L.; Dain, L.
Año de publicación
2011
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fuente
PLoS ONE 2011;6(1)
Materia
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
Nivel de accesibilidad
acceso abierto
Condiciones de uso
http://creativecommons.org/licenses/by/2.5/ar
Repositorio
Biblioteca Digital (UBA-FCEN)
Institución
Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales
OAI Identificador
paperaa:paper_19326203_v6_n1_p_Minutolo

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oai_identifier_str paperaa:paper_19326203_v6_n1_p_Minutolo
network_acronym_str BDUBAFCEN
repository_id_str 1896
network_name_str Biblioteca Digital (UBA-FCEN)
spelling Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patientsMinutolo, C.Nadra, A.D.Fernández, C.Taboas, M.Buzzalino, N.Casali, B.Belli, S.Charreau, E.H.Alba, L.Dain, L.cytochrome P450 2Ccytochrome P450 2C21steroid 21 monooxygenaseunclassified drugCYP21A2 protein, humansteroid 21 monooxygenasearticlechromosome 6pcongenital adrenal hyperplasiaexonframeshift mutationgene deletiongene mutationgenotypeheterozygote detectionhumannucleotide sequencephenotypepoint mutationpromoter regionprotein stabilityprotein structurepseudogenesalt wastingsequence analysissteroid 21 monooxygenase deficiencystructure analysisalgorithmArgentinacase control studychemical structurechemistrycongenital adrenal hyperplasiagenetic predispositiongeneticsmutationMammaliaAdrenal Hyperplasia, CongenitalAlgorithmsArgentinaCase-Control StudiesGenetic Predisposition to DiseaseHumansModels, MolecularMutationProtein StabilitySteroid 21-HydroxylaseCongenital 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.2011info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfhttp://hdl.handle.net/20.500.12110/paper_19326203_v6_n1_p_MinutoloPLoS ONE 2011;6(1)reponame:Biblioteca Digital (UBA-FCEN)instname:Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturalesinstacron:UBA-FCENenginfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/2.5/ar2025-09-29T13:43:09Zpaperaa:paper_19326203_v6_n1_p_MinutoloInstitucionalhttps://digital.bl.fcen.uba.ar/Universidad públicaNo correspondehttps://digital.bl.fcen.uba.ar/cgi-bin/oaiserver.cgiana@bl.fcen.uba.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:18962025-09-29 13:43:10.491Biblioteca Digital (UBA-FCEN) - Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturalesfalse
dc.title.none.fl_str_mv Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patients
title Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patients
spellingShingle Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patients
Minutolo, C.
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
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
dc.creator.none.fl_str_mv Minutolo, C.
Nadra, A.D.
Fernández, C.
Taboas, M.
Buzzalino, N.
Casali, B.
Belli, S.
Charreau, E.H.
Alba, L.
Dain, L.
author Minutolo, C.
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_role author
author2 Nadra, A.D.
Fernández, C.
Taboas, M.
Buzzalino, N.
Casali, B.
Belli, S.
Charreau, E.H.
Alba, L.
Dain, L.
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv 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
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
dc.description.none.fl_txt_mv 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.
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.
publishDate 2011
dc.date.none.fl_str_mv 2011
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12110/paper_19326203_v6_n1_p_Minutolo
url http://hdl.handle.net/20.500.12110/paper_19326203_v6_n1_p_Minutolo
dc.language.none.fl_str_mv eng
language eng
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/2.5/ar
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/2.5/ar
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv PLoS ONE 2011;6(1)
reponame:Biblioteca Digital (UBA-FCEN)
instname:Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales
instacron:UBA-FCEN
reponame_str Biblioteca Digital (UBA-FCEN)
collection Biblioteca Digital (UBA-FCEN)
instname_str Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales
instacron_str UBA-FCEN
institution UBA-FCEN
repository.name.fl_str_mv Biblioteca Digital (UBA-FCEN) - Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales
repository.mail.fl_str_mv ana@bl.fcen.uba.ar
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