Lack of F8 mRNA: a novel mechanism leading to hemophilia A.
Hemophilia A (HA) is caused by partial or total deficiency of F8 protein activity. In a small group, about 1.8% of patients with HA, no mutation is found in the F8 gene. Among this group, we report here on one patient with severe HA in whom no mRNA of the F8 gene was detected. Using 2 common polymorphisms in F8 exon 14, we were able to show that the same allele shared by the patient, his mother, and his sister was not detected by reverse transcription-polymerase chain reaction (RT-PCR) from total blood mRNA. Skewed X-chromosome inactivation in both the mother and the sister was excluded by studying the methylation profile of the androgen receptor gene (HUMARA locus). These findings strongly suggest that the cause of HA in this patient is either absence or rapid degradation of the F8 mRNA, which points to a novel mechanism leading to HA.
El-Maarri
Osman
O
Institute of Experimental Hematology and Transfusion Medicine, Sigmund Freud Str 25, 53127 Bonn, Germany. Osman.Elmaarri@ukb.uni-bonn.de
Singer
Heike
H
Klein
Claudia
C
Watzka
Matthias
M
Herbiniaux
Ursula
U
Brackmann
Hans H
HH
Schröder
Jörg
J
Graw
Jochen
J
Müller
Clemens R
CR
Schramm
Wolfgang
W
Schwaab
Rainer
R
Haaf
Thomas
T
Hanfland
Peter
P
Oldenburg
Johannes
J
D000293:Adolescent; D019175:DNA Methylation; D005169:Factor VIII / Q000235:genetics*; D005190:Family; D005260:Female; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics
D012333:RNA, Messenger; D011944:Receptors, Androgen; C078147:F8 protein, human; D005169:Factor VIII