Phenotype–genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivation

Autores
Radic, Claudia Pamela; Rossetti, Liliana Carmen; Abelleyro, Miguel Martin; Tetzlaff, T.; Candela, M.; Neme, D.; Sciuccati, G.; Bonduel, M.; Medina Acosta, E.; Larripa, Irene Beatriz; De Tezanos Pinto, M.; de Brasi, Carlos Daniel
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background: The recessive X-linked disorder hemophilia A (HA) is rarely expressed in female carriers, most of whom express about half of normal factor VIII activity (FVIII:C). Objective: To propose an integrative assessment model for the binary role of the phase between the mutated F8 and the active X-chromosome (Xa) in FVIII:C in HA carriers. Methods: We studied 67 females at risk of severe HA, comprising five symptomatic females (FVIII:C < 1.5 IU dL−1) and 14 controls. A correlation study between FVIII:C (observed vs. expected) and X-chromosome inactivation (XCI) patterns (XIPs; androgen receptor gene [AR] system) in blood leukocyte DNA was performed in carriers, by comparison of a model correlating FVIII:C and XIP with arbitrary models devoid of biological significance, and with FVIII:C levels in non-carriers (mean model) as a proxy from background data dispersion not influenced by XIP. Results: We provide proof-of-concept example from a family presenting with extremely skewed XIPs in which the severe HA phenotype appeared in a heterozygous carrier of a crossover between AR and F8 loci that phased the mutated F8 with the maternally inherited Xa. Furthermore, four cases of severe HA affected women who had a combination of a heterozygous F8 mutation and extremely skewed XIPs in leukocytes or oral mucosa are presented. Correlation analyses between FVIII:C levels and XIPs in carriers (n = 38) but not in non-carriers (n = 20) showed highly significant differences between the proposed correlation model and models without biological significance. The data support a binary influence of XCI, either increasing or decreasing the FVIII:C, subject to the underlying phase set between the F8 mutation and XCI. Conclusions: Our evidence suggests that the phase between XCI and mutated F8 acts as a molecular switch conditioning FVIII:C levels and HA expression in carriers.
Fil: Radic, Claudia Pamela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Rossetti, Liliana Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Abelleyro, Miguel Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Tetzlaff, T.. Universidad Nacional de General Sarmiento. Instituto de Ciencias; Argentina
Fil: Candela, M.. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; Argentina
Fil: Neme, D.. Fundación de la Hemofilia "Alfredo Pavlovsky"; Argentina
Fil: Sciuccati, G.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Bonduel, M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Medina Acosta, E.. Universidade Estadual Do Norte Fluminense Darcy Ribeiro; Brasil
Fil: Larripa, Irene Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: De Tezanos Pinto, M.. Fundación de la Hemofilia "Alfredo Pavlovsky"; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; Argentina
Fil: de Brasi, Carlos Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Materia
F8 Protein
Hemophilia A
X-Linked Genetic Diseases
X Chromosome Inactivation
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:11336/38691
Acceder
id CONICETDig_441c1ad602e36cdb7901ea75ac7f6436
oai_identifier_str oai:ri.conicet.gov.ar:11336/38691
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Phenotype–genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivationRadic, Claudia PamelaRossetti, Liliana CarmenAbelleyro, Miguel MartinTetzlaff, T.Candela, M.Neme, D.Sciuccati, G.Bonduel, M.Medina Acosta, E.Larripa, Irene BeatrizDe Tezanos Pinto, M.de Brasi, Carlos DanielF8 ProteinHemophilia AX-Linked Genetic DiseasesX Chromosome Inactivationhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Background: The recessive X-linked disorder hemophilia A (HA) is rarely expressed in female carriers, most of whom express about half of normal factor VIII activity (FVIII:C). Objective: To propose an integrative assessment model for the binary role of the phase between the mutated F8 and the active X-chromosome (Xa) in FVIII:C in HA carriers. Methods: We studied 67 females at risk of severe HA, comprising five symptomatic females (FVIII:C < 1.5 IU dL−1) and 14 controls. A correlation study between FVIII:C (observed vs. expected) and X-chromosome inactivation (XCI) patterns (XIPs; androgen receptor gene [AR] system) in blood leukocyte DNA was performed in carriers, by comparison of a model correlating FVIII:C and XIP with arbitrary models devoid of biological significance, and with FVIII:C levels in non-carriers (mean model) as a proxy from background data dispersion not influenced by XIP. Results: We provide proof-of-concept example from a family presenting with extremely skewed XIPs in which the severe HA phenotype appeared in a heterozygous carrier of a crossover between AR and F8 loci that phased the mutated F8 with the maternally inherited Xa. Furthermore, four cases of severe HA affected women who had a combination of a heterozygous F8 mutation and extremely skewed XIPs in leukocytes or oral mucosa are presented. Correlation analyses between FVIII:C levels and XIPs in carriers (n = 38) but not in non-carriers (n = 20) showed highly significant differences between the proposed correlation model and models without biological significance. The data support a binary influence of XCI, either increasing or decreasing the FVIII:C, subject to the underlying phase set between the F8 mutation and XCI. Conclusions: Our evidence suggests that the phase between XCI and mutated F8 acts as a molecular switch conditioning FVIII:C levels and HA expression in carriers.Fil: Radic, Claudia Pamela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Rossetti, Liliana Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Abelleyro, Miguel Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Tetzlaff, T.. Universidad Nacional de General Sarmiento. Instituto de Ciencias; ArgentinaFil: Candela, M.. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Neme, D.. Fundación de la Hemofilia "Alfredo Pavlovsky"; ArgentinaFil: Sciuccati, G.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Bonduel, M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Medina Acosta, E.. Universidade Estadual Do Norte Fluminense Darcy Ribeiro; BrasilFil: Larripa, Irene Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: De Tezanos Pinto, M.. Fundación de la Hemofilia "Alfredo Pavlovsky"; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: de Brasi, Carlos Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaWiley Blackwell Publishing, Inc2015-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/38691Radic, Claudia Pamela; Rossetti, Liliana Carmen; Abelleyro, Miguel Martin; Tetzlaff, T.; Candela, M.; et al.; Phenotype–genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivation; Wiley Blackwell Publishing, Inc; Journal of Thrombosis and Haemostasis; 13; 4; 4-2015; 530-5391538-7933CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1111/jth.12854/abstractinfo:eu-repo/semantics/altIdentifier/doi/10.1111/jth.12854info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:40:35Zoai:ri.conicet.gov.ar:11336/38691instacron: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:34982025-09-29 09:40:35.224CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Phenotype–genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivation
title Phenotype–genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivation
spellingShingle Phenotype–genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivation
Radic, Claudia Pamela
F8 Protein
Hemophilia A
X-Linked Genetic Diseases
X Chromosome Inactivation
title_short Phenotype–genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivation
title_full Phenotype–genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivation
title_fullStr Phenotype–genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivation
title_full_unstemmed Phenotype–genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivation
title_sort Phenotype–genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivation
dc.creator.none.fl_str_mv Radic, Claudia Pamela
Rossetti, Liliana Carmen
Abelleyro, Miguel Martin
Tetzlaff, T.
Candela, M.
Neme, D.
Sciuccati, G.
Bonduel, M.
Medina Acosta, E.
Larripa, Irene Beatriz
De Tezanos Pinto, M.
de Brasi, Carlos Daniel
author Radic, Claudia Pamela
author_facet Radic, Claudia Pamela
Rossetti, Liliana Carmen
Abelleyro, Miguel Martin
Tetzlaff, T.
Candela, M.
Neme, D.
Sciuccati, G.
Bonduel, M.
Medina Acosta, E.
Larripa, Irene Beatriz
De Tezanos Pinto, M.
de Brasi, Carlos Daniel
author_role author
author2 Rossetti, Liliana Carmen
Abelleyro, Miguel Martin
Tetzlaff, T.
Candela, M.
Neme, D.
Sciuccati, G.
Bonduel, M.
Medina Acosta, E.
Larripa, Irene Beatriz
De Tezanos Pinto, M.
de Brasi, Carlos Daniel
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv F8 Protein
Hemophilia A
X-Linked Genetic Diseases
X Chromosome Inactivation
topic F8 Protein
Hemophilia A
X-Linked Genetic Diseases
X Chromosome Inactivation
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background: The recessive X-linked disorder hemophilia A (HA) is rarely expressed in female carriers, most of whom express about half of normal factor VIII activity (FVIII:C). Objective: To propose an integrative assessment model for the binary role of the phase between the mutated F8 and the active X-chromosome (Xa) in FVIII:C in HA carriers. Methods: We studied 67 females at risk of severe HA, comprising five symptomatic females (FVIII:C < 1.5 IU dL−1) and 14 controls. A correlation study between FVIII:C (observed vs. expected) and X-chromosome inactivation (XCI) patterns (XIPs; androgen receptor gene [AR] system) in blood leukocyte DNA was performed in carriers, by comparison of a model correlating FVIII:C and XIP with arbitrary models devoid of biological significance, and with FVIII:C levels in non-carriers (mean model) as a proxy from background data dispersion not influenced by XIP. Results: We provide proof-of-concept example from a family presenting with extremely skewed XIPs in which the severe HA phenotype appeared in a heterozygous carrier of a crossover between AR and F8 loci that phased the mutated F8 with the maternally inherited Xa. Furthermore, four cases of severe HA affected women who had a combination of a heterozygous F8 mutation and extremely skewed XIPs in leukocytes or oral mucosa are presented. Correlation analyses between FVIII:C levels and XIPs in carriers (n = 38) but not in non-carriers (n = 20) showed highly significant differences between the proposed correlation model and models without biological significance. The data support a binary influence of XCI, either increasing or decreasing the FVIII:C, subject to the underlying phase set between the F8 mutation and XCI. Conclusions: Our evidence suggests that the phase between XCI and mutated F8 acts as a molecular switch conditioning FVIII:C levels and HA expression in carriers.
Fil: Radic, Claudia Pamela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Rossetti, Liliana Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Abelleyro, Miguel Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Tetzlaff, T.. Universidad Nacional de General Sarmiento. Instituto de Ciencias; Argentina
Fil: Candela, M.. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; Argentina
Fil: Neme, D.. Fundación de la Hemofilia "Alfredo Pavlovsky"; Argentina
Fil: Sciuccati, G.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Bonduel, M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Medina Acosta, E.. Universidade Estadual Do Norte Fluminense Darcy Ribeiro; Brasil
Fil: Larripa, Irene Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: De Tezanos Pinto, M.. Fundación de la Hemofilia "Alfredo Pavlovsky"; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; Argentina
Fil: de Brasi, Carlos Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
description Background: The recessive X-linked disorder hemophilia A (HA) is rarely expressed in female carriers, most of whom express about half of normal factor VIII activity (FVIII:C). Objective: To propose an integrative assessment model for the binary role of the phase between the mutated F8 and the active X-chromosome (Xa) in FVIII:C in HA carriers. Methods: We studied 67 females at risk of severe HA, comprising five symptomatic females (FVIII:C < 1.5 IU dL−1) and 14 controls. A correlation study between FVIII:C (observed vs. expected) and X-chromosome inactivation (XCI) patterns (XIPs; androgen receptor gene [AR] system) in blood leukocyte DNA was performed in carriers, by comparison of a model correlating FVIII:C and XIP with arbitrary models devoid of biological significance, and with FVIII:C levels in non-carriers (mean model) as a proxy from background data dispersion not influenced by XIP. Results: We provide proof-of-concept example from a family presenting with extremely skewed XIPs in which the severe HA phenotype appeared in a heterozygous carrier of a crossover between AR and F8 loci that phased the mutated F8 with the maternally inherited Xa. Furthermore, four cases of severe HA affected women who had a combination of a heterozygous F8 mutation and extremely skewed XIPs in leukocytes or oral mucosa are presented. Correlation analyses between FVIII:C levels and XIPs in carriers (n = 38) but not in non-carriers (n = 20) showed highly significant differences between the proposed correlation model and models without biological significance. The data support a binary influence of XCI, either increasing or decreasing the FVIII:C, subject to the underlying phase set between the F8 mutation and XCI. Conclusions: Our evidence suggests that the phase between XCI and mutated F8 acts as a molecular switch conditioning FVIII:C levels and HA expression in carriers.
publishDate 2015
dc.date.none.fl_str_mv 2015-04
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/11336/38691
Radic, Claudia Pamela; Rossetti, Liliana Carmen; Abelleyro, Miguel Martin; Tetzlaff, T.; Candela, M.; et al.; Phenotype–genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivation; Wiley Blackwell Publishing, Inc; Journal of Thrombosis and Haemostasis; 13; 4; 4-2015; 530-539
1538-7933
CONICET Digital
CONICET
url http://hdl.handle.net/11336/38691
identifier_str_mv Radic, Claudia Pamela; Rossetti, Liliana Carmen; Abelleyro, Miguel Martin; Tetzlaff, T.; Candela, M.; et al.; Phenotype–genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivation; Wiley Blackwell Publishing, Inc; Journal of Thrombosis and Haemostasis; 13; 4; 4-2015; 530-539
1538-7933
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1111/jth.12854/abstract
info:eu-repo/semantics/altIdentifier/doi/10.1111/jth.12854
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
dc.publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
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 13.070432

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