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Blood, 15 December 2000, Vol. 96, No. 13, pp. 4373-4375
BRIEF REPORT
Unbalanced X-chromosome inactivation with a novel FVIII gene
mutation resulting in severe hemophilia A in a female
Rémi Favier,
Jean-Maurice Lavergne,
Jean-Marc Costa,
Claudine Caron,
Claudine Mazurier,
Michèle Viémont,
Marc Delpech, and
Sophie Valleix
From the Service d'Hématologie Biologique,
Hôpital d'Enfants Armand Trousseau, Paris, France; Laboratoire
d'Hémostase et Thrombose. Unité INSERM U 143, Hôpital de Bicêtre, Le Kremlin Bicêtre, France;
Laboratoire de Biologie Moléculaire, Hôpital
Américain de Paris, Neuilly, France; Laboratoire
d'Hématologie, Hôpital Huriez, Lille, France; and
Laboratoire de Biochimie et Génétique Moléculaire,
Paris, France.
This report is of a 14-month-old girl affected with severe
hemophilia A. Both her parents had normal values for factor VIII activity, and von Willebrand disease type 2N was excluded. Karyotype analysis demonstrated no obvious alteration, and BclI
Southern blot did not reveal F8 gene inversions. Direct
sequencing of F8 gene exons revealed a frameshift-stop
mutation (Q565delC/ter566) in the heterozygous state in the proposita
only. F8 gene polymorphism analysis indicated that the
mutation must have occurred de novo in the paternal germline.
Furthermore, analysis of the pattern of X chromosome methylation at the
human androgen receptor gene locus demonstrated a skewed inactivation
of the derived maternal X chromosome from the lymphocytes of the
proband's DNA. Thus, the severe hemophilia A in the proposita results
from a de novo F8 gene frameshift-stop mutation on the
paternally derived X chromosome, associated with a nonrandom pattern of
inactivation of the maternally derived X chromosome.
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