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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)
AuthorsR Favier, J M Lavergne, J M Costa, C Caron, C Mazurier, M Viémont, M Delpech, S Valleix
JournalBlood (Blood) Vol. 96 Issue 13 Pg. 4373-5 (Dec 15 2000) ISSN: 0006-4971 [Print] United States
PMID11110718 (Publication Type: Case Reports, Journal Article)
Chemical References
  • Codon
  • Receptors, Androgen
  • von Willebrand Factor
  • Factor VIII
Topics
  • Child, Preschool
  • Codon (genetics)
  • DNA Methylation
  • Dosage Compensation, Genetic
  • Factor VIII (genetics, metabolism)
  • Female
  • Frameshift Mutation
  • Genomic Imprinting
  • Haplotypes (genetics)
  • Hemophilia A (genetics)
  • Humans
  • Lymphocytes (enzymology)
  • Receptors, Androgen (genetics)
  • Terminator Regions, Genetic
  • von Willebrand Factor (metabolism)

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