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

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.

Identification of Two Novel Fibrinogen Bβ Chain Mutations in Two Slovak Families with Quantitative Fibrinogen Disorders

“…Only in 20% of the more than 250 cases of congenital afibrinogenemia clinically described thus far have the causal mutations been identified [ 17 ]. Most of them (95%) are point mutations giving rise to null alleles originating from nonsense, small insertions and deletions, and splicing mutations [ 18 ]. The majority of alterations (55%) appear to be clustered in the Aα-chain gene.…”

Human Fibrinogen: Molecular and Genetic Aspects of Congenital Disorders

“…In a 28-year-old afibrinogenemic man presenting with mucocutaneous bleeding and blood losses into muscles, joints, and soft tissues, the Gln180Stop “Martin” variant was identified in FGB [ 43 , 44 ]. Naz and colleagues described the novel FGA p.Gln183stop and FGG p.Lys121stop nonsense variants in two afibrinogenemic patients from Pakistan [ 45 ]. Notably, nonsense variants identified in FGA sequences were never found in residues belonging to the alpha chain C-terminal end but mainly in exon 5.…”

Genetic Variants in the FGB and FGG Genes Mapping in the Beta and Gamma Nodules of the Fibrinogen Molecule in Congenital Quantitative Fibrinogen Disorders Associated with a Thrombotic Phenotype

“…Generally speaking, in populations with frequent consanguineous marriages, the prevalence of afibrinogenemia, and also the occurence of other disorders of hemostasis with autosomal recessive inheritance, is increased. Geographical differences in the prevalence reflect high occurence in children of consanguineous parents in Muslim countries [32].…”

“…The pathogenesis of afibrinogenemia at molecular level has long been clarified. It represents an autosomal recessive disorder [ 32 ] with heterozygote patients being without any clinical manifestation and identifiable as hypofibrinogenemic [ 1 ]. Afibrinogenemia is the consequence of bialleic mutations in the homozygous or compound heterozygous state in one of genes encoding for the fibrinogen chains.…”