A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic Steatohepatitis

Autores
Pirola, Carlos José; Flichman, Diego Martin; Dopazo, Hernán Javier; Fernández Gianotti, Tomás; San Martino, Julio; Rohr, Cristian Oscar; Garaycoechea, Martin; Gazzi, Carla; Castaño, Gustavo Osvaldo; Sookoian, Silvia Cristina
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
We report on the presence of a rare nonsense mutation (rs149847328, p.Arg227Ter) in the glucokinase regulator (GCKR) gene in an adult patient with nonalcoholic fatty liver disease (NAFLD), morbid obesity, and type 2 diabetes; this patient developed a progressive histological form of the disease. Analysis of paired (5 years apart) liver biopsies (at baseline and follow-up) showed progression of simple steatosis to severe nonalcoholic steatohepatitis and cirrhosis. Study design involved an initial exploration that consisted of deep sequencing of 14 chromosomal regions in 96 individuals (64 of whom were patients with NAFLD who were diagnosed by liver biopsy that showed the full spectrum of histological severity). We further performed a replication study to explore the presence of rs149847328 that included a sample of 517 unrelated individuals in a case-control study (n = 390), including patients who were morbidly obese (n = 127). Exploration of sequence variation by next-generation sequencing of exons, exon-intron boundaries, and 5´ and 3´ untranslated regions of 14 genomic loci that encode metabolic enzymes of the tricarboxylic acid cycle revealed the presence of heterozygosity for the p.Arg227Ter mutation, the frequency of which is 0.0003963 (4:10,000; Exome Aggregation Consortium database). GCKR protein expression was markedly decreased in the liver of the affected patient compared with patients with NAFLD who carry the wild-type allele. Sequencing of the same 14 genomic loci in 95 individuals failed to reveal the rare mutation. The rarity of p.Arg227Ter was confirmed in a more extensive screening. Conclusion: While rare variants/mutations are difficult to detect in even reasonably large samples (frequency of the mutant allele of p.Arg227Ter was ~1:1,000 in our data set), the presence of this mutation should be suspected as potentially associated with NAFLD, particularly in young adults at the extreme of histological phenotypes.
Fil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Flichman, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Fil: Dopazo, Hernán Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; Argentina
Fil: Fernández Gianotti, Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: San Martino, Julio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Rohr, Cristian Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; Argentina
Fil: Garaycoechea, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Gazzi, Carla. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Castaño, Gustavo Osvaldo. Gobierno de la Ciudad de Buenos Aires. Hospital "Dr. Abel Zubizarreta"; Argentina
Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Materia
GCKR
RARE VARIANT
NAFLD
NASH
MENDELIAN FORM
FATTY LIVER
FIBROSIS
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:11336/86753
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/86753
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic SteatohepatitisPirola, Carlos JoséFlichman, Diego MartinDopazo, Hernán JavierFernández Gianotti, TomásSan Martino, JulioRohr, Cristian OscarGaraycoechea, MartinGazzi, CarlaCastaño, Gustavo OsvaldoSookoian, Silvia CristinaGCKRRARE VARIANTNAFLDNASHMENDELIAN FORMFATTY LIVERFIBROSIShttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3We report on the presence of a rare nonsense mutation (rs149847328, p.Arg227Ter) in the glucokinase regulator (<i>GCKR</i>) gene in an adult patient with nonalcoholic fatty liver disease (NAFLD), morbid obesity, and type 2 diabetes; this patient developed a progressive histological form of the disease. Analysis of paired (5 years apart) liver biopsies (at baseline and follow-up) showed progression of simple steatosis to severe nonalcoholic steatohepatitis and cirrhosis. Study design involved an initial exploration that consisted of deep sequencing of 14 chromosomal regions in 96 individuals (64 of whom were patients with NAFLD who were diagnosed by liver biopsy that showed the full spectrum of histological severity). We further performed a replication study to explore the presence of rs149847328 that included a sample of 517 unrelated individuals in a case-control study (n = 390), including patients who were morbidly obese (n = 127). Exploration of sequence variation by next-generation sequencing of exons, exon-intron boundaries, and 5´ and 3´ untranslated regions of 14 genomic loci that encode metabolic enzymes of the tricarboxylic acid cycle revealed the presence of heterozygosity for the p.Arg227Ter mutation, the frequency of which is 0.0003963 (4:10,000; Exome Aggregation Consortium database). GCKR protein expression was markedly decreased in the liver of the affected patient compared with patients with NAFLD who carry the wild-type allele. Sequencing of the same 14 genomic loci in 95 individuals failed to reveal the rare mutation. The rarity of p.Arg227Ter was confirmed in a more extensive screening. <i>Conclusion:</i> While rare variants/mutations are difficult to detect in even reasonably large samples (frequency of the mutant allele of p.Arg227Ter was ~1:1,000 in our data set), the presence of this mutation should be suspected as potentially associated with NAFLD, particularly in young adults at the extreme of histological phenotypes.Fil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Flichman, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Dopazo, Hernán Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; ArgentinaFil: Fernández Gianotti, Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: San Martino, Julio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Rohr, Cristian Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; ArgentinaFil: Garaycoechea, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Gazzi, Carla. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Castaño, Gustavo Osvaldo. Gobierno de la Ciudad de Buenos Aires. Hospital "Dr. Abel Zubizarreta"; ArgentinaFil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaWiley2018-09info: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/11336/86753Pirola, Carlos José; Flichman, Diego Martin; Dopazo, Hernán Javier; Fernández Gianotti, Tomás; San Martino, Julio; et al.; A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic Steatohepatitis; Wiley; Hepatology Communications; 2; 9; 9-2018; 1030-10362471-254XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1002/hep4.1235info:eu-repo/semantics/altIdentifier/url/https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep4.1235info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:00:38Zoai:ri.conicet.gov.ar:11336/86753instacron: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:34982025-09-03 10:00:39.038CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic Steatohepatitis
title A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic Steatohepatitis
spellingShingle A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic Steatohepatitis
Pirola, Carlos José
GCKR
RARE VARIANT
NAFLD
NASH
MENDELIAN FORM
FATTY LIVER
FIBROSIS
title_short A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic Steatohepatitis
title_full A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic Steatohepatitis
title_fullStr A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic Steatohepatitis
title_full_unstemmed A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic Steatohepatitis
title_sort A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic Steatohepatitis
dc.creator.none.fl_str_mv Pirola, Carlos José
Flichman, Diego Martin
Dopazo, Hernán Javier
Fernández Gianotti, Tomás
San Martino, Julio
Rohr, Cristian Oscar
Garaycoechea, Martin
Gazzi, Carla
Castaño, Gustavo Osvaldo
Sookoian, Silvia Cristina
author Pirola, Carlos José
author_facet Pirola, Carlos José
Flichman, Diego Martin
Dopazo, Hernán Javier
Fernández Gianotti, Tomás
San Martino, Julio
Rohr, Cristian Oscar
Garaycoechea, Martin
Gazzi, Carla
Castaño, Gustavo Osvaldo
Sookoian, Silvia Cristina
author_role author
author2 Flichman, Diego Martin
Dopazo, Hernán Javier
Fernández Gianotti, Tomás
San Martino, Julio
Rohr, Cristian Oscar
Garaycoechea, Martin
Gazzi, Carla
Castaño, Gustavo Osvaldo
Sookoian, Silvia Cristina
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv GCKR
RARE VARIANT
NAFLD
NASH
MENDELIAN FORM
FATTY LIVER
FIBROSIS
topic GCKR
RARE VARIANT
NAFLD
NASH
MENDELIAN FORM
FATTY LIVER
FIBROSIS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv We report on the presence of a rare nonsense mutation (rs149847328, p.Arg227Ter) in the glucokinase regulator (<i>GCKR</i>) gene in an adult patient with nonalcoholic fatty liver disease (NAFLD), morbid obesity, and type 2 diabetes; this patient developed a progressive histological form of the disease. Analysis of paired (5 years apart) liver biopsies (at baseline and follow-up) showed progression of simple steatosis to severe nonalcoholic steatohepatitis and cirrhosis. Study design involved an initial exploration that consisted of deep sequencing of 14 chromosomal regions in 96 individuals (64 of whom were patients with NAFLD who were diagnosed by liver biopsy that showed the full spectrum of histological severity). We further performed a replication study to explore the presence of rs149847328 that included a sample of 517 unrelated individuals in a case-control study (n = 390), including patients who were morbidly obese (n = 127). Exploration of sequence variation by next-generation sequencing of exons, exon-intron boundaries, and 5´ and 3´ untranslated regions of 14 genomic loci that encode metabolic enzymes of the tricarboxylic acid cycle revealed the presence of heterozygosity for the p.Arg227Ter mutation, the frequency of which is 0.0003963 (4:10,000; Exome Aggregation Consortium database). GCKR protein expression was markedly decreased in the liver of the affected patient compared with patients with NAFLD who carry the wild-type allele. Sequencing of the same 14 genomic loci in 95 individuals failed to reveal the rare mutation. The rarity of p.Arg227Ter was confirmed in a more extensive screening. <i>Conclusion:</i> While rare variants/mutations are difficult to detect in even reasonably large samples (frequency of the mutant allele of p.Arg227Ter was ~1:1,000 in our data set), the presence of this mutation should be suspected as potentially associated with NAFLD, particularly in young adults at the extreme of histological phenotypes.
Fil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Flichman, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Fil: Dopazo, Hernán Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; Argentina
Fil: Fernández Gianotti, Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: San Martino, Julio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Rohr, Cristian Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; Argentina
Fil: Garaycoechea, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Gazzi, Carla. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Castaño, Gustavo Osvaldo. Gobierno de la Ciudad de Buenos Aires. Hospital "Dr. Abel Zubizarreta"; Argentina
Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
description We report on the presence of a rare nonsense mutation (rs149847328, p.Arg227Ter) in the glucokinase regulator (<i>GCKR</i>) gene in an adult patient with nonalcoholic fatty liver disease (NAFLD), morbid obesity, and type 2 diabetes; this patient developed a progressive histological form of the disease. Analysis of paired (5 years apart) liver biopsies (at baseline and follow-up) showed progression of simple steatosis to severe nonalcoholic steatohepatitis and cirrhosis. Study design involved an initial exploration that consisted of deep sequencing of 14 chromosomal regions in 96 individuals (64 of whom were patients with NAFLD who were diagnosed by liver biopsy that showed the full spectrum of histological severity). We further performed a replication study to explore the presence of rs149847328 that included a sample of 517 unrelated individuals in a case-control study (n = 390), including patients who were morbidly obese (n = 127). Exploration of sequence variation by next-generation sequencing of exons, exon-intron boundaries, and 5´ and 3´ untranslated regions of 14 genomic loci that encode metabolic enzymes of the tricarboxylic acid cycle revealed the presence of heterozygosity for the p.Arg227Ter mutation, the frequency of which is 0.0003963 (4:10,000; Exome Aggregation Consortium database). GCKR protein expression was markedly decreased in the liver of the affected patient compared with patients with NAFLD who carry the wild-type allele. Sequencing of the same 14 genomic loci in 95 individuals failed to reveal the rare mutation. The rarity of p.Arg227Ter was confirmed in a more extensive screening. <i>Conclusion:</i> While rare variants/mutations are difficult to detect in even reasonably large samples (frequency of the mutant allele of p.Arg227Ter was ~1:1,000 in our data set), the presence of this mutation should be suspected as potentially associated with NAFLD, particularly in young adults at the extreme of histological phenotypes.
publishDate 2018
dc.date.none.fl_str_mv 2018-09
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/11336/86753
Pirola, Carlos José; Flichman, Diego Martin; Dopazo, Hernán Javier; Fernández Gianotti, Tomás; San Martino, Julio; et al.; A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic Steatohepatitis; Wiley; Hepatology Communications; 2; 9; 9-2018; 1030-1036
2471-254X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/86753
identifier_str_mv Pirola, Carlos José; Flichman, Diego Martin; Dopazo, Hernán Javier; Fernández Gianotti, Tomás; San Martino, Julio; et al.; A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic Steatohepatitis; Wiley; Hepatology Communications; 2; 9; 9-2018; 1030-1036
2471-254X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1002/hep4.1235
info:eu-repo/semantics/altIdentifier/url/https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep4.1235
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 Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
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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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