Molecular genetics of haemostasis.
We are studying human genetic disorders of hemostasis, in particular fibrinogen deficiencies. These are rare and affect either the quantity or the quality of circulating fibrinogen, which is the precursor of the major protein component of the blood clot, fibrin. Our laboratory identified the gene and the first causative mutations for complete deficiency of fibrinogen, afibrinogenemia, in 1999. Fibrinogen is a hexamer comprising two copies of three polypeptides. These are encoded by the fibrinogen alpha, beta and gamma genes clustered on human chromosome 4. While still pursuing studies of the molecular mechanisms by which fibrinogen gene mutations lead to disease, we are also investigating the broader picture influencing fibrinogen levels (which are highly variable amongst individuals) with the aim of identifying new regulatory elements in the genomic landscape of the fibrinogen cluster. We are also determining whether microRNAs are involved in the fine-tuning of fibrinogen levels. Animal models i.e. the zebrafish (Danio rerio) are used in the course of these projects. The discovery of novel mechanisms determining fibrinogen levels in the circulation is clinically relevant since a high fibrinogen level is an independent risk factor for cardiovascular disease.