A new ADAMTS13 missense mutation (D1362V) in thrombotic thrombocytopenic purpura diagnosed during pregnancy

Autores
Calderazzo, Julio César; Kempfer, Ana Catalina; Powazniak, Yanina Paola; Lopez, Lleana R.; Sánchez Luceros, Analía Gabriela; Woods, Adriana Inés; Lazzari, María Ángela
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Thrombotic thrombocytopenic purpura (TTP) is a disease characterized by microvascular thrombosis, often associated with deficiency of ADAMTS13 activity. Hereditary TTP has been linked to mutations in the ADAMTS13 gene whereas the inhibition of ADAMTS13 activity by autoimmune antibodies has been associated with acquired TTP. We report the case of a woman with deficiency of ADAMTS13 activity that had been asymptomatic until her first severe TTP episode during her first pregnancy. Genetic analysis revealed a non described missense mutation of ADAMTS13. This mutation resulted in an aspartic acid to valine substitution (D1362V). To verify the mechanism of ADAMTS13 deficiency in this patient, the wild type and the D1362V ADAMTS13 mutant construct was expressed in HEK 293 cells. The D1362V substitution led to a defect of secretion (ADAMTS13 antigen level=8±3%, ADAMTS13 activity=0% in culture media), causing intracellular accumulation of the protease (ADAMTS13 antigen level=133±5%, ADAMTS13 activity=129±13%) compared to wild-type (WT) ADAMTS13 (ADAMTS13 antigen and activity=100%). The results showed that D1362V mutation in the second CUB (CUB-2) domain, encoded by exon 29, induces an ADAMTS13 plasmatic deficiency due to reduced secretion of the protease into the circulation. Our data suggested that the CUB-2 domain encoded by exon 29 is particularly important for ADAMTS13 secretion. Apparently, this severe ADAMTS13 plasmatic deficiency did not manage to lead to clinical manifestations given that the TTP triggering event was related to her first pregnancy.
Fil: Calderazzo, Julio César. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Kempfer, Ana Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Powazniak, Yanina Paola. Ministerio de Ciencia, Tecnología e Innovación Productiva. Agencia Nacional de Promoción Científica y Tecnológica. Fondo para la Investigación Científica y Tecnológica; Argentina
Fil: Lopez, Lleana R.. Hemobanco San Miguel de Tucuman; Argentina
Fil: Sánchez Luceros, Analía Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Woods, Adriana Inés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Lazzari, María Ángela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires; Argentina
Materia
Thrombotic Thrombocytopenic Purpura
Adamts13
Pregnancy
Cub-2 Domain
Site-Directed Mutagenesis
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:11336/53312
Acceder
id CONICETDig_98a2a4f706211c5bd9e4ec2fa2bbb6dd
oai_identifier_str oai:ri.conicet.gov.ar:11336/53312
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling A new ADAMTS13 missense mutation (D1362V) in thrombotic thrombocytopenic purpura diagnosed during pregnancyCalderazzo, Julio CésarKempfer, Ana CatalinaPowazniak, Yanina PaolaLopez, Lleana R.Sánchez Luceros, Analía GabrielaWoods, Adriana InésLazzari, María ÁngelaThrombotic Thrombocytopenic PurpuraAdamts13PregnancyCub-2 DomainSite-Directed Mutagenesishttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Thrombotic thrombocytopenic purpura (TTP) is a disease characterized by microvascular thrombosis, often associated with deficiency of ADAMTS13 activity. Hereditary TTP has been linked to mutations in the ADAMTS13 gene whereas the inhibition of ADAMTS13 activity by autoimmune antibodies has been associated with acquired TTP. We report the case of a woman with deficiency of ADAMTS13 activity that had been asymptomatic until her first severe TTP episode during her first pregnancy. Genetic analysis revealed a non described missense mutation of ADAMTS13. This mutation resulted in an aspartic acid to valine substitution (D1362V). To verify the mechanism of ADAMTS13 deficiency in this patient, the wild type and the D1362V ADAMTS13 mutant construct was expressed in HEK 293 cells. The D1362V substitution led to a defect of secretion (ADAMTS13 antigen level=8±3%, ADAMTS13 activity=0% in culture media), causing intracellular accumulation of the protease (ADAMTS13 antigen level=133±5%, ADAMTS13 activity=129±13%) compared to wild-type (WT) ADAMTS13 (ADAMTS13 antigen and activity=100%). The results showed that D1362V mutation in the second CUB (CUB-2) domain, encoded by exon 29, induces an ADAMTS13 plasmatic deficiency due to reduced secretion of the protease into the circulation. Our data suggested that the CUB-2 domain encoded by exon 29 is particularly important for ADAMTS13 secretion. Apparently, this severe ADAMTS13 plasmatic deficiency did not manage to lead to clinical manifestations given that the TTP triggering event was related to her first pregnancy.Fil: Calderazzo, Julio César. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Kempfer, Ana Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Powazniak, Yanina Paola. Ministerio de Ciencia, Tecnología e Innovación Productiva. Agencia Nacional de Promoción Científica y Tecnológica. Fondo para la Investigación Científica y Tecnológica; ArgentinaFil: Lopez, Lleana R.. Hemobanco San Miguel de Tucuman; ArgentinaFil: Sánchez Luceros, Analía Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Woods, Adriana Inés. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lazzari, María Ángela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires; ArgentinaSchattauer Gmbh-Verlag Medizin Naturwissenschaften2012-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/53312Calderazzo, Julio César; Kempfer, Ana Catalina; Powazniak, Yanina Paola; Lopez, Lleana R.; Sánchez Luceros, Analía Gabriela; et al.; A new ADAMTS13 missense mutation (D1362V) in thrombotic thrombocytopenic purpura diagnosed during pregnancy; Schattauer Gmbh-Verlag Medizin Naturwissenschaften; Thrombosis and Haemostasis; 108; 2; 8-2012; 401-4030340-6245CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1160/TH11-11-0783info:eu-repo/semantics/altIdentifier/url/https://www.thieme-connect.de/DOI/DOI?10.1160/TH11-11-0783info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T12:07:20Zoai:ri.conicet.gov.ar:11336/53312instacron: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 12:07:20.924CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv A new ADAMTS13 missense mutation (D1362V) in thrombotic thrombocytopenic purpura diagnosed during pregnancy
title A new ADAMTS13 missense mutation (D1362V) in thrombotic thrombocytopenic purpura diagnosed during pregnancy
spellingShingle A new ADAMTS13 missense mutation (D1362V) in thrombotic thrombocytopenic purpura diagnosed during pregnancy
Calderazzo, Julio César
Thrombotic Thrombocytopenic Purpura
Adamts13
Pregnancy
Cub-2 Domain
Site-Directed Mutagenesis
title_short A new ADAMTS13 missense mutation (D1362V) in thrombotic thrombocytopenic purpura diagnosed during pregnancy
title_full A new ADAMTS13 missense mutation (D1362V) in thrombotic thrombocytopenic purpura diagnosed during pregnancy
title_fullStr A new ADAMTS13 missense mutation (D1362V) in thrombotic thrombocytopenic purpura diagnosed during pregnancy
title_full_unstemmed A new ADAMTS13 missense mutation (D1362V) in thrombotic thrombocytopenic purpura diagnosed during pregnancy
title_sort A new ADAMTS13 missense mutation (D1362V) in thrombotic thrombocytopenic purpura diagnosed during pregnancy
dc.creator.none.fl_str_mv Calderazzo, Julio César
Kempfer, Ana Catalina
Powazniak, Yanina Paola
Lopez, Lleana R.
Sánchez Luceros, Analía Gabriela
Woods, Adriana Inés
Lazzari, María Ángela
author Calderazzo, Julio César
author_facet Calderazzo, Julio César
Kempfer, Ana Catalina
Powazniak, Yanina Paola
Lopez, Lleana R.
Sánchez Luceros, Analía Gabriela
Woods, Adriana Inés
Lazzari, María Ángela
author_role author
author2 Kempfer, Ana Catalina
Powazniak, Yanina Paola
Lopez, Lleana R.
Sánchez Luceros, Analía Gabriela
Woods, Adriana Inés
Lazzari, María Ángela
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Thrombotic Thrombocytopenic Purpura
Adamts13
Pregnancy
Cub-2 Domain
Site-Directed Mutagenesis
topic Thrombotic Thrombocytopenic Purpura
Adamts13
Pregnancy
Cub-2 Domain
Site-Directed Mutagenesis
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Thrombotic thrombocytopenic purpura (TTP) is a disease characterized by microvascular thrombosis, often associated with deficiency of ADAMTS13 activity. Hereditary TTP has been linked to mutations in the ADAMTS13 gene whereas the inhibition of ADAMTS13 activity by autoimmune antibodies has been associated with acquired TTP. We report the case of a woman with deficiency of ADAMTS13 activity that had been asymptomatic until her first severe TTP episode during her first pregnancy. Genetic analysis revealed a non described missense mutation of ADAMTS13. This mutation resulted in an aspartic acid to valine substitution (D1362V). To verify the mechanism of ADAMTS13 deficiency in this patient, the wild type and the D1362V ADAMTS13 mutant construct was expressed in HEK 293 cells. The D1362V substitution led to a defect of secretion (ADAMTS13 antigen level=8±3%, ADAMTS13 activity=0% in culture media), causing intracellular accumulation of the protease (ADAMTS13 antigen level=133±5%, ADAMTS13 activity=129±13%) compared to wild-type (WT) ADAMTS13 (ADAMTS13 antigen and activity=100%). The results showed that D1362V mutation in the second CUB (CUB-2) domain, encoded by exon 29, induces an ADAMTS13 plasmatic deficiency due to reduced secretion of the protease into the circulation. Our data suggested that the CUB-2 domain encoded by exon 29 is particularly important for ADAMTS13 secretion. Apparently, this severe ADAMTS13 plasmatic deficiency did not manage to lead to clinical manifestations given that the TTP triggering event was related to her first pregnancy.
Fil: Calderazzo, Julio César. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Kempfer, Ana Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Powazniak, Yanina Paola. Ministerio de Ciencia, Tecnología e Innovación Productiva. Agencia Nacional de Promoción Científica y Tecnológica. Fondo para la Investigación Científica y Tecnológica; Argentina
Fil: Lopez, Lleana R.. Hemobanco San Miguel de Tucuman; Argentina
Fil: Sánchez Luceros, Analía Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Woods, Adriana Inés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Lazzari, María Ángela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires; Argentina
description Thrombotic thrombocytopenic purpura (TTP) is a disease characterized by microvascular thrombosis, often associated with deficiency of ADAMTS13 activity. Hereditary TTP has been linked to mutations in the ADAMTS13 gene whereas the inhibition of ADAMTS13 activity by autoimmune antibodies has been associated with acquired TTP. We report the case of a woman with deficiency of ADAMTS13 activity that had been asymptomatic until her first severe TTP episode during her first pregnancy. Genetic analysis revealed a non described missense mutation of ADAMTS13. This mutation resulted in an aspartic acid to valine substitution (D1362V). To verify the mechanism of ADAMTS13 deficiency in this patient, the wild type and the D1362V ADAMTS13 mutant construct was expressed in HEK 293 cells. The D1362V substitution led to a defect of secretion (ADAMTS13 antigen level=8±3%, ADAMTS13 activity=0% in culture media), causing intracellular accumulation of the protease (ADAMTS13 antigen level=133±5%, ADAMTS13 activity=129±13%) compared to wild-type (WT) ADAMTS13 (ADAMTS13 antigen and activity=100%). The results showed that D1362V mutation in the second CUB (CUB-2) domain, encoded by exon 29, induces an ADAMTS13 plasmatic deficiency due to reduced secretion of the protease into the circulation. Our data suggested that the CUB-2 domain encoded by exon 29 is particularly important for ADAMTS13 secretion. Apparently, this severe ADAMTS13 plasmatic deficiency did not manage to lead to clinical manifestations given that the TTP triggering event was related to her first pregnancy.
publishDate 2012
dc.date.none.fl_str_mv 2012-08
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/11336/53312
Calderazzo, Julio César; Kempfer, Ana Catalina; Powazniak, Yanina Paola; Lopez, Lleana R.; Sánchez Luceros, Analía Gabriela; et al.; A new ADAMTS13 missense mutation (D1362V) in thrombotic thrombocytopenic purpura diagnosed during pregnancy; Schattauer Gmbh-Verlag Medizin Naturwissenschaften; Thrombosis and Haemostasis; 108; 2; 8-2012; 401-403
0340-6245
CONICET Digital
CONICET
url http://hdl.handle.net/11336/53312
identifier_str_mv Calderazzo, Julio César; Kempfer, Ana Catalina; Powazniak, Yanina Paola; Lopez, Lleana R.; Sánchez Luceros, Analía Gabriela; et al.; A new ADAMTS13 missense mutation (D1362V) in thrombotic thrombocytopenic purpura diagnosed during pregnancy; Schattauer Gmbh-Verlag Medizin Naturwissenschaften; Thrombosis and Haemostasis; 108; 2; 8-2012; 401-403
0340-6245
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1160/TH11-11-0783
info:eu-repo/semantics/altIdentifier/url/https://www.thieme-connect.de/DOI/DOI?10.1160/TH11-11-0783
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
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Schattauer Gmbh-Verlag Medizin Naturwissenschaften
publisher.none.fl_str_mv Schattauer Gmbh-Verlag Medizin Naturwissenschaften
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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