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dc.contributor.author Radic, Claudia Pamela
dc.contributor.author Rossetti, Liliana Carmen
dc.contributor.author Abelleyro, Miguel Martin
dc.contributor.author Tetzlaff, T.
dc.contributor.author Candela, M.
dc.contributor.author Neme, D.
dc.contributor.author Sciuccati, G.
dc.contributor.author Bonduel, M.
dc.contributor.author Medina Acosta, E.
dc.contributor.author Larripa, Irene Beatriz
dc.contributor.author De Tezanos Pinto, M.
dc.contributor.author de Brasi, Carlos Daniel
dc.date.available 2018-03-13T19:20:19Z
dc.date.issued 2015-04
dc.identifier.citation 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
dc.identifier.issn 1538-7933
dc.identifier.uri http://hdl.handle.net/11336/38691
dc.description.abstract 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.
dc.format application/pdf
dc.language.iso eng
dc.publisher Wiley Blackwell Publishing, Inc
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject F8 protein
dc.subject hemophilia A
dc.subject X-linked genetic diseases
dc.subject X chromosome inactivation
dc.subject.classification Inmunología
dc.subject.classification Medicina Básica
dc.subject.classification CIENCIAS MÉDICAS Y DE LA SALUD
dc.title Phenotype–genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivation
dc.type info:eu-repo/semantics/article
dc.type info:ar-repo/semantics/artículo
dc.type info:eu-repo/semantics/publishedVersion
dc.date.updated 2018-03-08T18:59:25Z
dc.journal.volume 13
dc.journal.number 4
dc.journal.pagination 530-539
dc.journal.pais Reino Unido
dc.journal.ciudad Londres
dc.description.fil 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
dc.description.fil 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
dc.description.fil 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
dc.description.fil Fil: Tetzlaff, T.. Universidad Nacional de General Sarmiento. Instituto de Ciencias; Argentina
dc.description.fil Fil: Candela, M.. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; Argentina
dc.description.fil Fil: Neme, D.. Fundación de la Hemofilia "Alfredo Pavlovsky"; Argentina
dc.description.fil Fil: Sciuccati, G.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
dc.description.fil Fil: Bonduel, M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
dc.description.fil Fil: Medina Acosta, E.. Universidade Estadual Do Norte Fluminense Darcy Ribeiro; Brasil
dc.description.fil 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
dc.description.fil 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
dc.description.fil 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
dc.journal.title Journal of Thrombosis and Haemostasis
dc.relation.alternativeid info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1111/jth.12854/abstract
dc.relation.alternativeid info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1111/jth.12854
dc.conicet.fuente individual


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info:eu-repo/semantics/restrictedAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)