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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
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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
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Fil: Neme, D.. Fundación de la Hemofilia "Alfredo Pavlovsky"; Argentina
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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


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