LIU Meina,SU Kankan,ZHANG Haiyue, et al. Phenotypic and genetic analysis of a pedigree with inherited protein C deficiency[J]. JOURNAL OF WEZHOU MEDICAL UNIVERSITY, 2019, 49(4): 277-280.
Abstract：Objective: To ascertain the mutant gene of a family with hereditary protein C (PC) deficiency and to explore the molecular pathogenesis. Methods: The plasma protein C activity (PC:A), protein C antigen (PC:Ag) and other coagulation index of the family members were measured. For the proband, potential mutations in exons, flanking introns and 5’, 3’untranslated regions of PROC gene were screened by direct DNA sequencing. The Mutational site was further detected in the other family members. The ClustalX-2.1-win software and the online bioinformatics tool PolyPhen-2 were used to checke the conservatism and the possible impact of the mutation respectively. Structural analysis of the mutational site was processed with software Swiss-PdbViewer and PIC program. Results: The proband, her son and sister had reduced level of PC:A and PC:Ag among 39%~58%. Gene sequencing revealed that three people carried a heterozygous mutation c.997G>A in exon 9 of PROC gene resulting in a substitution of Alanine 291 by Threonine (p.Ala291Thr). According to the results of bioinformatics software analysis, p.Ala291Thr was “probably damaging” and Ala291 was not highly conserved. Model analyzing illuminated that replacement of Ala291 with Thr291 led to additional hydrogen bonding between Thr291-Pro327, affecting the normal spatial conformation and stability of protein. Conclusion: The proband carried a heterozygous mutation c.997G>A in exon 9 resulting in p.Ala291Thr which is a novel mutation. The p.Ala291Thr mutation could potentially account for the reduced activity of PC in this pedigree.
[1] BRUECKMANN M, HOFFMANN U, DE R L, et al. Activated protein C inhibits the release of macrophage inflammatory protein-1-alpha from THP-1 cells and from human monocytes[J]. Cytokine, 2004, 26(3): 106-113.
[2] KROISS S, ALBISETTI M. Use of human protein C concentrates in the treatment of patients with severe congenital protein C deficiency[J]. Biologics, 2010, 4(24): 51-60.
[3] 杨丽红, 金艳慧, 杨婷, 等. 两个遗传性蛋白C缺陷症家系表型与基因突变分析[J]. 中华医学遗传学杂志, 2017, 34(1): 10-14.
[4] BUCCIARELLI P, PASSAMONTI S M, BIGUZZI E, et al. Low borderline plasma levels of antithrombin, protein C and protein S are risk factors for venous thromboembolism[J]. J Thromb Haemost, 2012, 10(9): 1783-1791.
[5] DE A K, PAL S, DAS S, et al. Protein C deficiency[J]. Indian J Hematol Blood Transfus, 2014, 30(Suppl 1): 142-144.
[6] WYPASEK E, UNDAS A. Protein C and protein S deficiency-practical diagnostic issues[J]. Adv Clin Exp Med, 2013, 22(4): 459-467.
[7] GU Y, SHEN W, ZHANG L, et al. Deficiency of antithrombin and protein C gene in 202 Chinese venous thromboembolism patients[J]. Int J Lab Hematol, 2014, 36(2): 151-155.
[8] 刘昌妍, 王晓非, 张晓莉, 等. 系统性红斑狼疮患者中活化蛋白C抵抗的测定及临床意义[J]. 中国医科大学学报, 2012, 41(4): 354-356.
[9] WU Y T, YUE F, WANG M, et a1. Hereditary protein C deficiency caused by compound heterozygous mutants in two independent Chinese families[J]. Pathology, 2014, 46(7): 630-635.
[10] 沈薇, 顾怡, 张岚, 等. 20例蛋白C缺陷静脉血栓患者的PROC基因调查[J]. 中华医学杂志, 2012, 92(23): 1603-1606.
[11] GALE A J, TSAVALER A, GRIFFIN J H. Molecular characterization of an extended binding site for coagulation factor Va in the positive exosite of activated protein C[J]. Biol Chem, 2002, 277(32): 28836-28840.
[12] KERSCHEN E J, FERNADEZ J A, COOLY B C, et al. Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C[J]. Exp Med, 2007, 204(10): 2439-2448.
