Investigation of novel mechanisms causing F8 deficiency in haemophilia A patients without mutation in the F8 cDNA

• Applicant: Privatdozent Dr. Osman El-Maarri
• Subject Area: Hematology, Oncology
• Term: from 2008 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 72476541

In the healthy population the F8 activity levels are variable. It is known that high levels of F8 activity expose to a higher risk for thrombosis, while extreme low levels cause haemophilia. Studying large number of about 2400 haemophilia A patients that count for 1/3 of all patients in Germany we previously identified a unique cohort of a small percentage of patients (3% or about 80 individuals) with no mutations in the coding sequence of F8. We proposed earlier that in some of these patients a very low expression of F8 could be responsible for the haemophilia phenotype. In this project we will follow this work and in addition will address other potential mutations mechanisms by Southern blot, mRNA analysis and small/micro RNAs together with other coagulation parameters that could influence the variability of the F8 levels in plasma. In addition abnormal rearrangements or mutations inside the F8 introns will be investigated by sequencing of the entire F8 genomic region. Our study will results in an improved understanding of novel mechanisms that lead to variability of F8 levels in normal and disease conditions. Moreover by studying this unique and highly selective group of patients we will provide a model for other single gene diseases where the mutations are still unknown in a sub cohort. Thus our project provides a unique opportunity to characterize less common and still unknown mutation mechanisms.

• DFG Programme: Research Grants
• Participating Person: Professor Johannes Oldenburg, Ph.D.