Identification of novel mutations in congenital afibrinogenemia patients and molecular modeling of missense mutations in Pakistani population

Thrombosis Journal

Research

Nisar Ahmed¹  Nazish Saqlain¹  Arijit Biswas²  Johannes Oldenburg³  Ikram Din Ujjan⁴  Arshi Naz⁵  Shariq Ahmed⁶  Tehmina Nafees Khan⁶  Tahir S Shamsi⁶  Anne Goodeve⁷ 

[1] Children’s Hospital, Resident, Paediatric hematology, Main Ferozpur Road, Lahore, Pakistan;Institute of Experimental Hematology and Transfusion Medicine, Bonn, Germany;Institute of Experimental Hematology and Transfusion Medicine, AG, FXIII Room No. 2.308 Sigmund Freud Street-25, 53127, Bonn, Germany;Institute of Experimental Hematology and Transfusion Medicine, Bonn, Germany;Institute of Experimental Hematology and Transfusion Medicine, Sigmund Freud Street-25, 53127, Bonn, Germany;Liaquat university of medical and health sciences, Jamshoro, Pakistan;National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi University of Bonn, ST 2/A, Block-17, Gulshan-e-Iqbal KDA scheme, 24, Karachi, Pakistan;National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi University of Bonn, ST 2/A, Block-17, Gulshan-e-Iqbal KDA scheme, 24, Karachi, Pakistan;National Institute of blood diseases and bone marrow transplantation, ST 2/A, Block-17, Gulshan-e-Iqbal KDA scheme, 24, Karachi, Pakistan;University of Shieffield, Shiefield, United Kingdom;Clinical Scientist and Professor of Molecular Medicine, Sheffield Diagnostic Genetics Service, Sheffield Children’s NHS Foundation Trust, Western Bank, S10 2TH, Sheffield, UK;

关键词: Afibrinogenemia;    Molecular modeling;    FGA;    Consanguinity;    Inherited bleeding disorder;   

DOI  :  10.1186/s12959-017-0143-3

 received in 2016-11-09, accepted in 2017-06-28,  发布年份 2017

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s). 2017