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Molecular mechanisms underlying hemophilia A phenotype in seven females
Author(s) -
PAVLOVA A.,
BRONDKE H.,
MÜSEBECK J.,
POLLMANN H.,
SRIVASTAVA A.,
OLDENBURG J.
Publication year - 2009
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2009.03346.x
Subject(s) - missense mutation , genetics , multiplex ligation dependent probe amplification , exon , biology , phenotype , x inactivation , gene , compound heterozygosity , mutation , loss of heterozygosity , sanger sequencing , microbiology and biotechnology , x chromosome , allele
Summary. 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 Thr2272 fs ) 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.