Studies On The Genetic Mutations Of Hereditary Fibrinogen Disorder And Hereditary FXI Deficiency

Hereditary fibrinogen disorder is a rare kind of bleeding disease, which divided into two types. Type I is a kind of quantity disorder, including afibrinogenemia and hypofibrinogenemia. Type II is a kind of quality disorder, including dysfibrinogenemia. Fibrinogen is a kind of hexameric glycoprotein and consists of two pairs of three chains, which are Aa,Bβ and ychain. FGA^ FGB and FGG code for the glycoprotein. The mutations on those are responsible for this disorder. The number of mutation is over three hundreds, including nonsense mutation, missense mutation, frameshift mutation and so on, which are mainly located in exons. Hot spots happen to this disorder, mainly located in Arg16 in the Aa chain and Arg275 in the y chain, which have effect on assembly of fibrinogen monomer and then on the function of fibrinogen. In this study, firstly, we performed experiment for detecting the level of fibrinogen antigen of 12 cases with low fibrinogen activity. The result showed that one case has low level, definded as hypofibeinogenemia, and other 11 cases have normal level, named as dysfibrinogenemia. Following by, we perfomed gene detecting and the result showed that among 11 cases with dysfibrinogenemia, five harbored AaArgl6His heterozygous mutation and one of those also possessed yAspl85Asn heterozygous mutation, unreported so far; one AaArgl6Cys heterozygous mutation; four yArg275Cys heterozygous mutation; one yArg275His heterozygous mutation. One case with hypofibrinogenemia harbored AaCys36Arg heterozygous mutation. And then we continued to do further research about the novel mutation (yAsp185Asn). We failed to find normal controls harbor the novel mutation. In molecular modeling, we found that the hydrogen bonds were changed in the mutation variant. Besides, a new site of glycosylation may appear after mutation. Above all, the stability of molecular structure may be destroyed. The contrast of homologous sequence between different species suggested that this is a highly conservative site.Hereditary FXI disorder is also a rare bleeding disease, the incidence of which is 1/1 000 000. There is heterogeneity of the incidence among different race. This disease is the most popular among Ashkenazi Jewish population. The mutation on the Fll coding for FXI led to this disorder. There is no apparently relation between the activities and bleeding. Patient with low activity of FXI rarely experience bleeding. Most of patients were identified during routine coagulant test. In our study, two cases having prolonged APTT were tested the activity of intrinsic and extrinsic coagulant factors. Except for FXI, the activity was normal. We detected genetic mutation on these two cases. The result showed that one harbored Val-12TrpfsX15 homozygous mutation and the other one Trp228Stop heterozygous mutation and Glu323Lys heterozygous mutation. Due to the lack of other family members in the latter, we had no idea about whether the two mutations are in the same chromosome. Due to the very low activity of FXI of the patient, we speculated these two mutations are in the different chromosome and regarded as compound heterozygous mutations.In this paper, we performed studies on the genetic mutation of 12 cases with hereditary fibrinogen disorder and two cases with hereditary FXI disorder, and then we draw conclusions as follow:1、Among cases with hereditary fibrinogen disorder, we further identified hot spots(Argl6 in the Aa chain and Arg275 in the y chain), which were found in the 11 cases with dysfibrinogenemia. These mutations had negative effect on the function of fibrinogen, so the level of antigen was normal. One case with AaCys36Arg heterozygous mutation has low level of antigen, which suggested the important of disulfide bond for secretion of fibrinogen.2、The further analysis of a novel mutation (yAspl85Asn) may suggest that this one was responsible for hereditary fibrinogen disorder.3、The variants of Val-12TrpfsX15、Trp228Stop and Glu323Lys in F11 were responsible for two cases with hereditary FXI disorder. The former was firstly reported, which made translation to stop in advance, and we consider it responsible for the disorder in case one.The latter two were responsible for case two, reported by other teams.