Objective: To investigate the molecular etiology of protein C (PC) deficiency. Methods: Routine diagnosis and genetic analysis were performed on four probands with PC deficiency. Results: ①Case 1, female, 40 years old, diagnosed of deep vein thrombosis in left lower limb. PC activity (PC∶C) was 48%, PS activity (PS∶C) was 26.3%, AT activity (AT∶C) was 75.6%. Genetic analysis discovered heterozygous mutation C5156T on promoter of PC gene, together with heterozygous mutation A6578T on Exon2 of PC gene. After anticoagulant, thrombolysis and filter implantation therapies, the patient went home with improvement. ②Case 2, female, 32 years old, diagnosed of deep vein thrombosis in both lower limb, ischemia in both lower and upper limb, and skin infection in both lower limb. PC∶C 27%, PS∶C 22.9%, AT∶C 86.7%. Genetic analysis identified heterozygous mutation C5156T, together with heterozygous mutation A5045T on promoter of PC gene. After anticoagulant and anti-infection therapy, the patient died of respiratory failure, septic shock and DIC. ③Case 3, female, 28 years old, diagnosed of vein thrombosis in right iliac and femoral vein. PC∶C 58%, PS∶C 57.3% , AT∶C 80.8%. Genetic analysis disclosed heterozygous mutation C4867T on promoter of PC gene, AGA 12702-12704del or 12705-12707del on Exon7, the latter one lead to Arg192 or 193del. Heterozygous mutation G15240A on Exon9 was also found. After anticoagulant, thrombolysis and filter implantation therapies, the patient went home with improvement. ④Case 4, male, 30 years old, diagnosed of vein thrombosis in right iliac and femoral vein. PC∶C 50%, PS∶C 75.0%, AT∶C 89.1%. Genetic analysis found homozygous mutation C4867T and G4880A on promoter of PC gene, heterozygous mutation A5045T on promoter and heterozygous mutation T6589C on Exon2. After anticoagulant, thrombolysis and filter implantation therapies, the patient went home with improvement. ⑤ Polymorphism analysis revealed that heterozygous mutation C4867T, homozygous mutation G4880A, and heterozygous mutation C5156T were polymorphism sites of PC gene. Conclusions: Polymorphism sites (G4880A, C4867T, C5156T), missense mutation A5045T, A6578T, G15240A, and deletion mutation AGA12702-12704del, 12705-12707del may be related to deficiency of PC. Missense mutation A5045T, A6578T, G15240A, and deletion mutation AGA12702-12704, 12705-12707del were first reported worldwide.
目的: 探讨蛋白C缺陷症的分子发病机制。
方法: 对4例蛋白C缺陷症患者进行常规诊断和基因分析。
结果: ①例1，女，40岁。临床诊断：左下肢深静脉血栓形成。蛋白C活性（PC∶C）48%，蛋白S活性（PS∶C）26.3%，抗凝血酶活性（AT∶C) 75.6%。基因检测结果：蛋白C基因（PROC）启动子C5156T杂合突变、2号外显子区域存在A6578T杂合突变。给予抗凝、溶栓、滤器植入等治疗，症状好转出院。②例2，女，32岁。临床诊断：双下肢深静脉血栓，双上、下肢缺血，双下肢皮肤软组织感染。PC∶C 27%，PS∶C 22.9%，AT∶C 86.7%。基因检测结果：PROC基因启动子C5156T杂合突变、A5045T杂合突变。给予抗凝、抗感染等治疗，因呼吸衰竭、感染性休克、DIC死亡。③例3，女，28岁。临床诊断：右髂静脉及股深静脉血栓。PC∶C 58%，PS∶C 57.3%，AT∶C 80.8%。基因检测结果：PROC启动子C4867T杂合突变，7号外显子12702-12704 AGA (Arg192）或12705-12707 AGA（Arg193）杂合缺失，9号外显子G15240A杂合突变。给予抗凝、溶栓、滤器植入等治疗，症状好转出院。④例4，男，30岁。临床诊断：左下肢深静脉血栓，双下肺动脉栓塞伴双下肺梗死。PC∶C 50%，PS∶C 75.0%，AT∶C 89.1%。基因检测结果：PROC启动子C4867T纯合突变、G4880A纯合突变和A5045T杂合突变，2号外显子T6589C杂合突变。给予抗凝、溶栓、滤器植入等相关治疗，症状好转出院。⑤多态性分析：PROC基因启动子C4867T杂合突变、G4880A纯合突变、C5156T杂合突变为PROC启动子多态性位点。
结论: PROC启动子多态性位点G4880A、C4867T、C5156T，错义突变A5045T、A6578T、G15240A，缺失突变AGA12702-12704del或12705-12707del可能与蛋白C缺陷症有关。PROC启动子错义突变A5045T、A6578T、G15240A，缺失突变AGA12702-12704del或12705-12706del是国际首次报告。