Investigation of Underlying Reasons of Factor VIM Deficiency in Hemophilia A Patients with Undetectable Mutations in the F8 Gene

摘要

Hemophilia A (HA) is an X-linked bleeding disorder caused by heterogeneous mutations in the coagulation factor VIII (F8) gene [4]. Despite applying sensitive methods for mutation detection, and after excluding the inversions mutations a causative mutation is not identified in F8 gene in about 2.5% of severe HA patients (53 patients out of 2350 German patients) (unpublished data). Analysis of mRNA from a small group of such (German) patients has excluded mutations deep in the introns that may affect normal splicing or mechanisms causing some unknown rearrangements of the F8 gene as the cause of HA [1]. Among this group, in one patient no F8 mRNA was detected [2]. Using two 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 PCR (RT-PCR) from total blood mRNA. 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. Recently we established an international multi-centre collaborative study to assemble a large collection of such families.