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

Autores
Minutolo, Carolina; Nadra, Alejandro D.; Fernández, Cecilia; Taboas, Melisa; Buzzalino, Noemí; Casali, Bárbara; Belli, Susana; Charreau, Eduardo H.; Alba, Liliana; Dain, Liliana
Año de publicación
2011
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Fil: Minutolo, Carolina. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
Fil: Nadra, Alejandro D. Universidad de Buenos Aires. Departamento de Fisiología Biología Molecular y Celular; Argentina.
Fil: Fernández, Cecilia. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
Fil: Taboas, Melisa. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
Fil: Buzzalino, Noemí. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
Fil: Casali, Bárbara. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
Fil: Belli, Susana. Hospital Durand. División Endocrinología; Argentina.
Fil: Charreau, Eduardo H. Instituto de Biología y Medicina Experimental; Argentina.
Fil: Alba, Liliana. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
Fil: Dain, Liliana. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
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.
Fuente
PloS One 2011; 6(1): e15899.
Materia
Mutación
Esteroide 21-Hidroxilasa
Nivel de accesibilidad
acceso abierto
Condiciones de uso
Repositorio
Sistema de Gestión del Conocimiento ANLIS MALBRÁN
Institución
Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán"
OAI Identificador
oai:sgc.anlis.gob.ar:123456789/397

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spelling Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patientsMinutolo, CarolinaNadra, Alejandro D.Fernández, CeciliaTaboas, MelisaBuzzalino, NoemíCasali, BárbaraBelli, SusanaCharreau, Eduardo H.Alba, LilianaDain, LilianaMutaciónEsteroide 21-HidroxilasaFil: Minutolo, Carolina. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Nadra, Alejandro D. Universidad de Buenos Aires. Departamento de Fisiología Biología Molecular y Celular; Argentina.Fil: Fernández, Cecilia. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Taboas, Melisa. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Buzzalino, Noemí. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Casali, Bárbara. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Belli, Susana. Hospital Durand. División Endocrinología; Argentina.Fil: Charreau, Eduardo H. Instituto de Biología y Medicina Experimental; Argentina.Fil: Alba, Liliana. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Dain, Liliana. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.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.Yes2011info:ar-repo/semantics/articuloinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdf1932-6203http://sgc.anlis.gob.ar/handle/123456789/397http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3019215/pdf/pone.0015899.pdf10.1371/journal.pone.0015899.PloS One 2011; 6(1): e15899.reponame:Sistema de Gestión del Conocimiento ANLIS MALBRÁNinstname:Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán"instacron:ANLISPlos oneenginfo:eu-repo/semantics/openAccess2025-09-29T14:29:59Zoai:sgc.anlis.gob.ar:123456789/397Institucionalhttp://sgc.anlis.gob.ar/Organismo científico-tecnológicoNo correspondehttp://sgc.anlis.gob.ar/oai/biblioteca@anlis.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:a2025-09-29 14:30:00.539Sistema de Gestión del Conocimiento ANLIS MALBRÁN - Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán"false
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, Carolina
Mutación
Esteroide 21-Hidroxilasa
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, Carolina
Nadra, Alejandro D.
Fernández, Cecilia
Taboas, Melisa
Buzzalino, Noemí
Casali, Bárbara
Belli, Susana
Charreau, Eduardo H.
Alba, Liliana
Dain, Liliana
author Minutolo, Carolina
author_facet Minutolo, Carolina
Nadra, Alejandro D.
Fernández, Cecilia
Taboas, Melisa
Buzzalino, Noemí
Casali, Bárbara
Belli, Susana
Charreau, Eduardo H.
Alba, Liliana
Dain, Liliana
author_role author
author2 Nadra, Alejandro D.
Fernández, Cecilia
Taboas, Melisa
Buzzalino, Noemí
Casali, Bárbara
Belli, Susana
Charreau, Eduardo H.
Alba, Liliana
Dain, Liliana
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Mutación
Esteroide 21-Hidroxilasa
topic Mutación
Esteroide 21-Hidroxilasa
dc.description.none.fl_txt_mv Fil: Minutolo, Carolina. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
Fil: Nadra, Alejandro D. Universidad de Buenos Aires. Departamento de Fisiología Biología Molecular y Celular; Argentina.
Fil: Fernández, Cecilia. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
Fil: Taboas, Melisa. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
Fil: Buzzalino, Noemí. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
Fil: Casali, Bárbara. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
Fil: Belli, Susana. Hospital Durand. División Endocrinología; Argentina.
Fil: Charreau, Eduardo H. Instituto de Biología y Medicina Experimental; Argentina.
Fil: Alba, Liliana. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
Fil: Dain, Liliana. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
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.
description Fil: Minutolo, Carolina. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.
publishDate 2011
dc.date.none.fl_str_mv 2011
dc.type.none.fl_str_mv info:ar-repo/semantics/articulo
info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv 1932-6203
http://sgc.anlis.gob.ar/handle/123456789/397
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3019215/pdf/pone.0015899.pdf
10.1371/journal.pone.0015899.
identifier_str_mv 1932-6203
10.1371/journal.pone.0015899.
url http://sgc.anlis.gob.ar/handle/123456789/397
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3019215/pdf/pone.0015899.pdf
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Plos one
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Yes
publisher.none.fl_str_mv Yes
dc.source.none.fl_str_mv PloS One 2011; 6(1): e15899.
reponame:Sistema de Gestión del Conocimiento ANLIS MALBRÁN
instname:Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán"
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instname_str Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán"
instacron_str ANLIS
institution ANLIS
repository.name.fl_str_mv Sistema de Gestión del Conocimiento ANLIS MALBRÁN - Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán"
repository.mail.fl_str_mv biblioteca@anlis.gov.ar
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