Phenotype-genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivation.
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.
['Radic|C P|CP|', 'Rossetti|L C|LC|', 'Abelleyro|M M|MM|', 'Tetzlaff|T|T|', 'Candela|M|M|', 'Neme|D|D|', 'Sciuccati|G|G|', 'Bonduel|M|M|', 'Medina-Acosta|E|E|', 'Larripa|I B|IB|', 'de Tezanos Pinto|M|M|', 'De Brasi|C D|CD|']
D000293:Adolescent D000328:Adult D016022:Case-Control Studies D002648:Child D002675:Child, Preschool D041321:Chromosomes, Human, X D005169:Factor VIII D005260:Female D056726:Genetic Association Studies D005819:Genetic Markers D020022:Genetic Predisposition to Disease D006467:Hemophilia A D040941:Heredity D006579:Heterozygote D006801:Humans D007223:Infant D008875:Middle Aged D009154:Mutation D010375:Pedigree D010641:Phenotype D011944:Receptors, Androgen D012307:Risk Factors D012720:Severity of Illness Index D049951:X Chromosome Inactivation D055815:Young Adult
hemophilia A F8 protein, human X chromosome X chromosome inactivation X-linked genetic diseases