Abstract
BackgroundCongenital afibrinogenemia (OMIM #202400) is a rare coagulation disorder that was first described in 1920. It is transmitted as an autosomal recessive trait that is characterized by absent levels of fibrinogen (factor I) in plasma. Consanguinity in Pakistan and its neighboring countries has resulted in a higher number of cases of congenital fibrinogen deficiency in their respective populations. This study focused on the detection of mutations in fibrinogen genes using DNA sequencing and molecular modeling of missense mutations in all three genes [Fibrinogen gene alpha (FGA), beta (FGB) and gamma (FGG)] in Pakistani patients.MethodsThis descriptive and cross sectional study was conducted in Karachi and Lahore and fully complied with the Declaration of Helsinki. Patients with fibrinogen deficiency were screened for mutations in the Fibrinogen 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.ResultsTen patients had mutations in FGA followed by three mutations in FGB and three mutations in FGG, respectively. Twelve of these mutations were novel. The missense mutations were predicted to result in a loss of stability because they break ordered regions and cause clashes in the hydrophobic core of the protein.ConclusionsCongenital afibrinogenemia is a rapidly growing problem in regions where consanguinity is frequently practiced. This study illustrates that mutations in FGA are relatively more common in Pakistani patients and molecular modeling of the missense mutations has shown damaging protein structures which has profounding effect on phenotypic bleeding manifestations in these patients.
Highlights
Congenital afibrinogenemia (OMIM #202400) is a rare coagulation disorder that was first described in 1920
Naz et al Thrombosis Journal (2017) 15:24 three pairs (Aα, Bβ and Gγ) of polypeptide chains [5] encoded by three genes (FGA, Fibrinogen gene beta (FGB) and Fibrinogen gene gamma (FGG)) clustered in a region of approximately 50 kb on chromosome 4q28q31 [6, 7]
The major bulk of identified mutations is present in Fibrinogen gene alpha (FGA) gene which tends to be the most frequently occurring mutation site in our study population
Summary
Congenital afibrinogenemia (OMIM #202400) is a rare coagulation disorder that was first described in 1920. It is transmitted as an autosomal recessive trait that is characterized by absent levels of fibrinogen (factor I) in plasma. Hemostasis is the normal physiological response that prevents blood loss following vascular injury. It is dependent on an intricate series of events involving platelets and specific coagulation factors. Inherited bleeding disorders can be grouped into abnormalities of primary and secondary hemostasis. The fibrin meshwork traps red blood cells and platelets to form a plug which stops bleeding from site of injury. The most common symptom associated with fibrinogen deficiency is umbilical stump bleeding with other secondary bleeding manifestations including epistaxis, gum bleeding, cutaneous bleeding, muscle hematoma and haemarthrosis [13]
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