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
- Institución
- Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales
- OAI Identificador
- paperaa:paper_19326203_v6_n1_p_Minutolo
Ver los metadatos del registro completo
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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 |
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Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales |
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UBA-FCEN |
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UBA-FCEN |
repository.name.fl_str_mv |
Biblioteca Digital (UBA-FCEN) - Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales |
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