title: Molecular mechanisms underlying hemophilia A phenotype in seven females.
abstract: BACKGROUND
  Hemophilia A (HA) in females is a rare observation. Here we describe various genetic mechanisms that result in phenotypic expression of HA in seven females.
  
  
  METHODS
  The F8 gene was examined in all patients and relatives by direct sequencing. Multiplex ligation-dependent probe amplification (MLPA) was performed for large deletion screening. X chromosome inactivation was studied by PCR analysis of a polymorphic CAG repeat in the first exon of the human androgen receptor (HUMARA) gene.
  
  
  RESULTS
  In two females sequencing of the F8 gene revealed homozygous missense mutations (Arg593Cys and Tyr1680Phe) as a consequence of consanguineous marriage. The third case was due to compound heterozygosity comprising the missense mutation Leu412Phe inherited from the carrier mother, together with a de novo large deletion spanning exon 9-22, probably originating from the germ cells of the healthy father. Three further cases shared a common mechanism representing heterozygous mutations in the F8 gene (Arg1781His, Arg327His, small deletion in exon 10) combined with non-random inactivation of the X chromosome. The final case describes a coincidental inheritance of HA and Coffin-Lowry syndrome in the same family. The HA phenotype results from a heterozygous small deletion affecting the F8 gene (c.6872 del CT leading to Thr2272fs) and a complete inactivation of the maternal X chromosome, which segregates with Coffin-Lowry syndrome in the two brothers of the proposita.
  
  
  CONCLUSIONS
  In conclusion, molecular genetic analysis represents an essentially valuable tool in elucidating the nature of the molecular mechanisms underlying the HA phenotype in females.
authors.affiliation: Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Pavlova
authors.forename: H
authors.initials: H
authors.lastname: Brondke
authors.forename: J
authors.initials: J
authors.lastname: Müsebeck
authors.forename: H
authors.initials: H
authors.lastname: Pollmann
authors.forename: A
authors.initials: A
authors.lastname: Srivastava
authors.forename: J
authors.initials: J
authors.lastname: Oldenburg
mesh_terms: D000328:Adult; D002675:Child, Preschool; D005260:Female; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D049951:X Chromosome Inactivation