Identification of Novel Mutations with Molecular Modelling of Missense Mutations of Congenital Afibrinogenemia Patients in Pakistan

Background:

Congenital afibrinogenemia (OMIM #202400) is a rare coagulation disorder which was first described in 1920. It is transmitted as an autosomal recessive trait characterized by absent levels of fibrinogen (factor I) in plasma. Consanguinity in Pakistan and its neighboring countries has resulted in higher cases of congenital fibrinogen deficiency in their respective populations.

Aims: This study focuses on the detection of mutations in the fibrinogen genes by DNA sequencing and molecular modeling of missense mutations in all three genes (Fibrinogen gene alpha (FGA), beta (FGB) and gamma (FGG) in Pakistani patients.

Methods:

This descriptive and cross sectional study was conducted in Karachi and Lahore and fully complied with the Declaration of Helsinki. Patients with fibrinogen deficiency (tested by Fibrinogen functional assay from Laboratoire Stago, Asnieres, France) were screened for mutations in the Fibrinogen gene alpha (FGA), beta (FGB) and gamma (FGG) genes by direct sequencing. Molecular modeling was performed to predict the putative structure functional impact of the missense mutations identified in this study

Results:

Ten patients had FGA mutations, four have FGB mutations and one mutation was detected in FGG. Thirteen of these mutations were novel. The missense mutations are predicted to result in loss of stability since they (a) break ordered regions (b) cause clashes in the hydrophobic core of the protein.

Conclusion:

Congenital afibrinogenemia is a rapid growing problem in countries such as Pakistan where consanguinity is frequently practiced. This study illustrates the fact that mutations in FGA are relatively more common in our population than those in FGB where as FGG mutations appear rarer.