| Protein C, a vitamin K-dependent glycoprotein and a zymogen of a serine protease, plays a critical role in the regulation of blood coagulation. Activated protein C can specifically degrade factor V (V ) and VIII (VIIIa). Genetic abnormality or some acquired factors may cause protein C deficiency, which may be a contributing cause of deep vein thrombophilia often in conjunction with other genetic or acquired risk factors.Protein C is a common cause of recurrent Deep Vein Thrombosis (DVT) , which was first reported by Geriffin et al. Up to now more than 300 clinical cases and 130 unique mutations about human protein C deficiency were reported. Due to so many unique mutations and limited measurement of detecting protein C deficiency, the molecular mechanism of deep vein thrombosis caused by protein C deficiency is not clear. Research in this field mainly was done in America and Europe. Fortunately, we found a family with a history of DVT, which happened without evident cause. And then we tried to find out whether there are some genetic disorders of protein C gene in this family. By DNA sequencing, we found five missense mutations and a deletion in exon9 from sevens family members within three generations. Six mutations are T11066-C (ATC-ACC, Ile407-Thr), A10789-G (ACC-GCC, Thr315-Ala), A10598-G (AGC-GGC, Ser252-Gly), G10645-C (GCC-CCC, Ala267-Pro), T10847-C (GTC-GCC, Val334-Ala) in coding region and an A 11172 deletion in 3' untranslated region(UTR) of exon9.Mutations T11066-C (Ile407-Thr) and A10598-G (Ser252-Gly) cause radical changes in chemical properties regarding to the amino acid side chain, which also leads to different type and number of H-bonds (hydrogen bonds) and change the consequential protein conformational freedom and make the protein C moleculars fold incorrectly. Subsequently these aberrant moleculars can't interact with some downstream proteins and fall off from Golgiosome or endoplasimic reticulum, which may cause these protein C moleculars unable to integrate with certain molecular chaperons and finally degrade in cells before their secreting into plasma: Additionally, the figure of heavy chain of protein C is like a ball, residue Ile407 and Ser252 lie on the surface of human protein C, so the radical changes of chemical properties of these two amino acid residues may also change the local domain structure, and then may influence the whole structure of humanprotein C.Mutation An 172 deletion lies in UTR, whereas it is so close to the site of polyadenylylation or cleavage of human protein C mRNA precursor. According to a novel genetic mechanism comtributing to hereditary thrombosis reported by Gehring et al, we speculated that mutation AH 172 deletion may affects the mRNA precursor processing and final protein C synthesis, but it still need further proof.In contrast to the above three mutations, mutation Gio645-C (Ala267-"Pro), Tios47 C (Val334-Ala) and A10789-G (Thr315-Ala) may have less dramatic effect on the structure of protein C because the change of chemical properties of amino acid residues, the change of type and number of H-bond and the effect of positions change according amino acid residues are less dramatic than the above three mutations.In addition, we found no mutation in the coding region of exon8, 7 and 3.Combination with above results and clinical resources, we concluded that mutation T11066-C (Ile407-Thr), A10598-G (Ser252-Gly) may cause protein C moleculars can't fold correctly and degrade in cells before their secreting into plasma. Mutation A11172 deletion may change the structure of mRNA precursor, leading to the aberration of mRNA precursor processing and the final protein C synthesis. So we thought these three mutations may account for the high risk of DVT in this family.The sequence of exon9 showed high variability either in patients with DVT or asymptomatic relatives in this explored family. It's the first time that we reported these six mutations about human protein C gene. |
PDF Full Text Request