An Intron 9 CYP19 Gene Variant (IVS9+5G>A), Present in an Aromatase-Deficient Girl, Affects Normal Splicing and Is Also Present in Normal Human Steroidogenic Tissues

Autores
Saraco, Nora Isabel; Nesi Franca, Suzana; Sainz, Romina Belén; Marino, Roxana Marcela; Marques Pereira, Rosana; La Pastina, Julia; Perez Garrido, Natalia; Sandrini, Romolo; Rivarola, Marco Aurelio; Lacerda, Luiz de; Belgorosky, Alicia
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background/Aims: Splicing CYP19 gene variants causingaromatase deficiency in 46,XX disorder of sexual development(DSD) patients have been reported in a few cases. Amisbalance between normal and aberrant splicing variants was proposed to explain spontaneous pubertal breast developmentbut an incomplete sex maturation progress. Theaim of this study was to functionally characterize a novelCYP19A1 intronic homozygote mutation (IVS9+5G>A) in a46,XX DSD girl presenting spontaneous breast developmentand primary amenorrhea, and to evaluate similar splicing variant expression in normal steroidogenic tissues. Methods:Genomic DNA analysis, splicing prediction programs,splicing assays, and in vitro protein expression and enzymeactivity analyses were carried out. CYP19A1 mRNA expressionin human steroidogenic tissues was also studied. Results:A novel IVS9+5G>A homozygote mutation was found.In silico analysis predicts the disappearance of the splicingdonor site in intron 9, confirmed by patient peripheral leukocytecP450arom and in vitro studies. Protein analysisshowed a shorter and inactive protein. The intron 9 transcriptvariant was also found in human steroidogenic tissues.Conclusions: The mutation IVS9+5G>A generates a splicingvariant that includes intron 9 which is also present in normalhuman steroidogenic tissues, suggesting that a misbalancebetween normal and aberrant splicing variants might occurin target tissues, explaining the clinical phenotype in the affectedpatient.
Fil: Saraco, Nora Isabel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Nesi Franca, Suzana. Universidade Federal do Paraná; Brasil
Fil: Sainz, Romina Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; Argentina
Fil: Marino, Roxana Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; Argentina
Fil: Marques Pereira, Rosana. Universidade Federal do Paraná; Brasil
Fil: La Pastina, Julia. Universidade Federal do Paraná; Brasil
Fil: Perez Garrido, Natalia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; Argentina
Fil: Sandrini, Romolo. Universidade Federal do Paraná; Brasil
Fil: Rivarola, Marco Aurelio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; Argentina
Fil: Lacerda, Luiz de. Universidade Federal do Paraná; Brasil
Fil: Belgorosky, Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; Argentina
Materia
Aromatase Deficiency
Mutation
Cyp19a1
Steroidogenic Tissues
Splicing
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/41793
Acceder
id CONICETDig_32ae477129ef1575a7f4c51c5fdbabc4
oai_identifier_str oai:ri.conicet.gov.ar:11336/41793
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling An Intron 9 CYP19 Gene Variant (IVS9+5G>A), Present in an Aromatase-Deficient Girl, Affects Normal Splicing and Is Also Present in Normal Human Steroidogenic TissuesSaraco, Nora IsabelNesi Franca, SuzanaSainz, Romina BelénMarino, Roxana MarcelaMarques Pereira, RosanaLa Pastina, JuliaPerez Garrido, NataliaSandrini, RomoloRivarola, Marco AurelioLacerda, Luiz deBelgorosky, AliciaAromatase DeficiencyMutationCyp19a1Steroidogenic TissuesSplicinghttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Background/Aims: Splicing CYP19 gene variants causingaromatase deficiency in 46,XX disorder of sexual development(DSD) patients have been reported in a few cases. Amisbalance between normal and aberrant splicing variants was proposed to explain spontaneous pubertal breast developmentbut an incomplete sex maturation progress. Theaim of this study was to functionally characterize a novelCYP19A1 intronic homozygote mutation (IVS9+5G>A) in a46,XX DSD girl presenting spontaneous breast developmentand primary amenorrhea, and to evaluate similar splicing variant expression in normal steroidogenic tissues. Methods:Genomic DNA analysis, splicing prediction programs,splicing assays, and in vitro protein expression and enzymeactivity analyses were carried out. CYP19A1 mRNA expressionin human steroidogenic tissues was also studied. Results:A novel IVS9+5G>A homozygote mutation was found.In silico analysis predicts the disappearance of the splicingdonor site in intron 9, confirmed by patient peripheral leukocytecP450arom and in vitro studies. Protein analysisshowed a shorter and inactive protein. The intron 9 transcriptvariant was also found in human steroidogenic tissues.Conclusions: The mutation IVS9+5G>A generates a splicingvariant that includes intron 9 which is also present in normalhuman steroidogenic tissues, suggesting that a misbalancebetween normal and aberrant splicing variants might occurin target tissues, explaining the clinical phenotype in the affectedpatient.Fil: Saraco, Nora Isabel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Nesi Franca, Suzana. Universidade Federal do Paraná; BrasilFil: Sainz, Romina Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; ArgentinaFil: Marino, Roxana Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; ArgentinaFil: Marques Pereira, Rosana. Universidade Federal do Paraná; BrasilFil: La Pastina, Julia. Universidade Federal do Paraná; BrasilFil: Perez Garrido, Natalia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; ArgentinaFil: Sandrini, Romolo. Universidade Federal do Paraná; BrasilFil: Rivarola, Marco Aurelio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; ArgentinaFil: Lacerda, Luiz de. Universidade Federal do Paraná; BrasilFil: Belgorosky, Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; ArgentinaKarger2015-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/41793Saraco, Nora Isabel; Nesi Franca, Suzana; Sainz, Romina Belén; Marino, Roxana Marcela; Marques Pereira, Rosana; et al.; An Intron 9 CYP19 Gene Variant (IVS9+5G>A), Present in an Aromatase-Deficient Girl, Affects Normal Splicing and Is Also Present in Normal Human Steroidogenic Tissues; Karger; Hormone Research in Paediatrics; 84; 4; 8-2015; 275-2821663-2826CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1159/000437142info:eu-repo/semantics/altIdentifier/url/https://www.karger.com/Article/Abstract/437142info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:01:26Zoai:ri.conicet.gov.ar:11336/41793instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:01:26.839CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv An Intron 9 CYP19 Gene Variant (IVS9+5G>A), Present in an Aromatase-Deficient Girl, Affects Normal Splicing and Is Also Present in Normal Human Steroidogenic Tissues
title An Intron 9 CYP19 Gene Variant (IVS9+5G>A), Present in an Aromatase-Deficient Girl, Affects Normal Splicing and Is Also Present in Normal Human Steroidogenic Tissues
spellingShingle An Intron 9 CYP19 Gene Variant (IVS9+5G>A), Present in an Aromatase-Deficient Girl, Affects Normal Splicing and Is Also Present in Normal Human Steroidogenic Tissues
Saraco, Nora Isabel
Aromatase Deficiency
Mutation
Cyp19a1
Steroidogenic Tissues
Splicing
title_short An Intron 9 CYP19 Gene Variant (IVS9+5G>A), Present in an Aromatase-Deficient Girl, Affects Normal Splicing and Is Also Present in Normal Human Steroidogenic Tissues
title_full An Intron 9 CYP19 Gene Variant (IVS9+5G>A), Present in an Aromatase-Deficient Girl, Affects Normal Splicing and Is Also Present in Normal Human Steroidogenic Tissues
title_fullStr An Intron 9 CYP19 Gene Variant (IVS9+5G>A), Present in an Aromatase-Deficient Girl, Affects Normal Splicing and Is Also Present in Normal Human Steroidogenic Tissues
title_full_unstemmed An Intron 9 CYP19 Gene Variant (IVS9+5G>A), Present in an Aromatase-Deficient Girl, Affects Normal Splicing and Is Also Present in Normal Human Steroidogenic Tissues
title_sort An Intron 9 CYP19 Gene Variant (IVS9+5G>A), Present in an Aromatase-Deficient Girl, Affects Normal Splicing and Is Also Present in Normal Human Steroidogenic Tissues
dc.creator.none.fl_str_mv Saraco, Nora Isabel
Nesi Franca, Suzana
Sainz, Romina Belén
Marino, Roxana Marcela
Marques Pereira, Rosana
La Pastina, Julia
Perez Garrido, Natalia
Sandrini, Romolo
Rivarola, Marco Aurelio
Lacerda, Luiz de
Belgorosky, Alicia
author Saraco, Nora Isabel
author_facet Saraco, Nora Isabel
Nesi Franca, Suzana
Sainz, Romina Belén
Marino, Roxana Marcela
Marques Pereira, Rosana
La Pastina, Julia
Perez Garrido, Natalia
Sandrini, Romolo
Rivarola, Marco Aurelio
Lacerda, Luiz de
Belgorosky, Alicia
author_role author
author2 Nesi Franca, Suzana
Sainz, Romina Belén
Marino, Roxana Marcela
Marques Pereira, Rosana
La Pastina, Julia
Perez Garrido, Natalia
Sandrini, Romolo
Rivarola, Marco Aurelio
Lacerda, Luiz de
Belgorosky, Alicia
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Aromatase Deficiency
Mutation
Cyp19a1
Steroidogenic Tissues
Splicing
topic Aromatase Deficiency
Mutation
Cyp19a1
Steroidogenic Tissues
Splicing
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background/Aims: Splicing CYP19 gene variants causingaromatase deficiency in 46,XX disorder of sexual development(DSD) patients have been reported in a few cases. Amisbalance between normal and aberrant splicing variants was proposed to explain spontaneous pubertal breast developmentbut an incomplete sex maturation progress. Theaim of this study was to functionally characterize a novelCYP19A1 intronic homozygote mutation (IVS9+5G>A) in a46,XX DSD girl presenting spontaneous breast developmentand primary amenorrhea, and to evaluate similar splicing variant expression in normal steroidogenic tissues. Methods:Genomic DNA analysis, splicing prediction programs,splicing assays, and in vitro protein expression and enzymeactivity analyses were carried out. CYP19A1 mRNA expressionin human steroidogenic tissues was also studied. Results:A novel IVS9+5G>A homozygote mutation was found.In silico analysis predicts the disappearance of the splicingdonor site in intron 9, confirmed by patient peripheral leukocytecP450arom and in vitro studies. Protein analysisshowed a shorter and inactive protein. The intron 9 transcriptvariant was also found in human steroidogenic tissues.Conclusions: The mutation IVS9+5G>A generates a splicingvariant that includes intron 9 which is also present in normalhuman steroidogenic tissues, suggesting that a misbalancebetween normal and aberrant splicing variants might occurin target tissues, explaining the clinical phenotype in the affectedpatient.
Fil: Saraco, Nora Isabel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Nesi Franca, Suzana. Universidade Federal do Paraná; Brasil
Fil: Sainz, Romina Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; Argentina
Fil: Marino, Roxana Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; Argentina
Fil: Marques Pereira, Rosana. Universidade Federal do Paraná; Brasil
Fil: La Pastina, Julia. Universidade Federal do Paraná; Brasil
Fil: Perez Garrido, Natalia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; Argentina
Fil: Sandrini, Romolo. Universidade Federal do Paraná; Brasil
Fil: Rivarola, Marco Aurelio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; Argentina
Fil: Lacerda, Luiz de. Universidade Federal do Paraná; Brasil
Fil: Belgorosky, Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; Argentina
description Background/Aims: Splicing CYP19 gene variants causingaromatase deficiency in 46,XX disorder of sexual development(DSD) patients have been reported in a few cases. Amisbalance between normal and aberrant splicing variants was proposed to explain spontaneous pubertal breast developmentbut an incomplete sex maturation progress. Theaim of this study was to functionally characterize a novelCYP19A1 intronic homozygote mutation (IVS9+5G>A) in a46,XX DSD girl presenting spontaneous breast developmentand primary amenorrhea, and to evaluate similar splicing variant expression in normal steroidogenic tissues. Methods:Genomic DNA analysis, splicing prediction programs,splicing assays, and in vitro protein expression and enzymeactivity analyses were carried out. CYP19A1 mRNA expressionin human steroidogenic tissues was also studied. Results:A novel IVS9+5G>A homozygote mutation was found.In silico analysis predicts the disappearance of the splicingdonor site in intron 9, confirmed by patient peripheral leukocytecP450arom and in vitro studies. Protein analysisshowed a shorter and inactive protein. The intron 9 transcriptvariant was also found in human steroidogenic tissues.Conclusions: The mutation IVS9+5G>A generates a splicingvariant that includes intron 9 which is also present in normalhuman steroidogenic tissues, suggesting that a misbalancebetween normal and aberrant splicing variants might occurin target tissues, explaining the clinical phenotype in the affectedpatient.
publishDate 2015
dc.date.none.fl_str_mv 2015-08
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/11336/41793
Saraco, Nora Isabel; Nesi Franca, Suzana; Sainz, Romina Belén; Marino, Roxana Marcela; Marques Pereira, Rosana; et al.; An Intron 9 CYP19 Gene Variant (IVS9+5G>A), Present in an Aromatase-Deficient Girl, Affects Normal Splicing and Is Also Present in Normal Human Steroidogenic Tissues; Karger; Hormone Research in Paediatrics; 84; 4; 8-2015; 275-282
1663-2826
CONICET Digital
CONICET
url http://hdl.handle.net/11336/41793
identifier_str_mv Saraco, Nora Isabel; Nesi Franca, Suzana; Sainz, Romina Belén; Marino, Roxana Marcela; Marques Pereira, Rosana; et al.; An Intron 9 CYP19 Gene Variant (IVS9+5G>A), Present in an Aromatase-Deficient Girl, Affects Normal Splicing and Is Also Present in Normal Human Steroidogenic Tissues; Karger; Hormone Research in Paediatrics; 84; 4; 8-2015; 275-282
1663-2826
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1159/000437142
info:eu-repo/semantics/altIdentifier/url/https://www.karger.com/Article/Abstract/437142
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Karger
publisher.none.fl_str_mv Karger
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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