title: Unbalanced X-chromosome inactivation with a novel FVIII gene mutation resulting in severe hemophilia A in a female.
abstract: 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. (Blood. 2000;96:4373-4375)
authors: Service d'Hématologie Biologique, Hôpital d'Enfants Armand Trousseau, Paris, France.
authors: R
authors: R
authors: Favier
authors: J M
authors: JM
authors: Lavergne
authors: J M
authors: JM
authors: Costa
authors: C
authors: C
authors: Caron
authors: C
authors: C
authors: Mazurier
authors: M
authors: M
authors: Viémont
authors: M
authors: M
authors: Delpech
authors: S
authors: S
authors: Valleix
mesh_terms: D002675:Child, Preschool; D003062:Codon / Q000235:genetics; D019175:DNA Methylation; D004303:Dosage Compensation, Genetic; D005169:Factor VIII / Q000235:genetics* / Q000378:metabolism; D005260:Female; D016368:Frameshift Mutation; D018392:Genomic Imprinting; D006239:Haplotypes / Q000235:genetics; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology; D011944:Receptors, Androgen / Q000235:genetics; D013728:Terminator Regions, Genetic; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D003062:Codon; D011944:Receptors, Androgen; D014841:von Willebrand Factor; D005169:Factor VIII