Analysis of a pedigree affected with congenital hypofibrinogenemia due to heterozygous Ser313Ile mutation of fibrinogen γ chain gene / 中华医学遗传学杂志

ABSTRACT

<p><b>OBJECTIVE</b>To explore the genetic basis for a Chinese pedigree affected with congenital hypofibrinogenamia.</p><p><b>METHODS</b>Peripheral blood samples were collected from 9 members from the pedigree. Routine coagulation tests including activated partial thromboplastin time (APTT), thrombin time (TT), the prothrombin time (PT) were carried out. The activity of fibrinogen (Fg C) was measured using Clauss method, and fibrinogen antigen (Fg Ag) was measured with immunoturbidimetry. All exons and exon-intron boundaries of the fibrinogen Aα, Bβ and γ chain genes were amplified using PCR, which was followed by direct sequencing. Suspected mutation was confirmed by reverse sequencing. The mutant fibrinogen was analyzed with Swiss-PdbViewer.</p><p><b>RESULTS</b>The proband showed prolonged APTT, PT and TT. Her functional fibrinogen (Fg C) and antigen fibrinogen (Fg Ag) levels were reduced to 0.69 g/L and 0.72 g/L, respectively. Her mother and grandmother also had a low levels of fibrinogen, which were 0.99 g/L and 0.83 g/L for Fg C, 1.02 g/L and 0.87 g/L for Fg Ag, respectively. The results of other members from the pedigree were all within the normal range. Genetic analysis reveled a heterozygous G>T mutation at nucleotide 7590 in exon 8 of γ gene in the proband, which was predicted to be a novel Ser313Ile mutation. The mutation was also found in her mother and grandmother. Model analysis showed that the Ser313Ile mutation disturbed the hydrogen bonds between Ser313, Asn319 and Asp320. Moreover, the mutation also altered the mutual electrostatic force and affected the folding and instability of the mutant fibrinogen.</p><p><b>CONCLUSION</b>The heterozygous Ser313Ile mutation probably underlies the hypofibrinogenemia in this pedigree.</p>