title: Phenotype-genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivation.
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 (
  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
  C in HA carriers.
  
  
  METHODS
  We studied 67 females at risk of severe HA, comprising five symptomatic females (
  C < 1.5 IU dL(-1) ) and 14 controls. A correlation study between
  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
  C and XIP with arbitrary models devoid of biological significance, and with
  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
  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
  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
  C levels and HA expression in carriers.
authors.affiliation: Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: C P
authors.initials: CP
authors.lastname: Radic
authors.forename: L C
authors.initials: LC
authors.lastname: Rossetti
authors.forename: M M
authors.initials: MM
authors.lastname: Abelleyro
authors.forename: T
authors.initials: T
authors.lastname: Tetzlaff
authors.forename: M
authors.initials: M
authors.lastname: Candela
authors.forename: D
authors.initials: D
authors.lastname: Neme
authors.forename: G
authors.initials: G
authors.lastname: Sciuccati
authors.forename: M
authors.initials: M
authors.lastname: Bonduel
authors.forename: E
authors.initials: E
authors.lastname: Medina-Acosta
authors.forename: I B
authors.initials: IB
authors.lastname: Larripa
authors.forename: M
authors.initials: M
authors.lastname: de Tezanos Pinto
authors.forename: C D
authors.initials: CD
authors.lastname: De Brasi
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X; D005169:Factor VIII / Q000032:analysis / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006467:Hemophilia A / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D040941:Heredity; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011944:Receptors, Androgen / Q000235:genetics; D012307:Risk Factors; D012720:Severity of Illness Index; D049951:X Chromosome Inactivation; D055815:Young Adult
chemical_list: C410798:AR protein, human; D005819:Genetic Markers; D011944:Receptors, Androgen; C078147:F8 protein, human; D005169:Factor VIII
keywords: F8 protein, human; X chromosome; X chromosome inactivation; X-linked genetic diseases; hemophilia A