Key Laboratory of Shenzhen Respiratory Diseases, Department of Pulmonary and Critical Care Medicine, Institute of Shenzhen Respiratory Diseases, The First Affiliated Hospital of Southern University of Science and Technology, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong, China.
The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China.
J Cell Mol Med. 2019 Oct;23(10):7099-7104. doi: 10.1111/jcmm.14563. Epub 2019 Jul 23.
Pathogenic mutation of protein C (PROC) gene results into the deficiency of PROC activity. This study aimed to identify the pathogenic genetic variants and to explore the functional consequence in Chinese familial venous thrombosis (VTE). Whole exome sequencing was performed to identify the pathogenic variants of anticoagulant factors. Serum coagulation and anti-coagulation factors activity were assayed to evaluate the genetic association. Functional study of PROC antigen secretion deficiency was conducted in VTE subjects and in vitro cell lines. One rare pathogenic variant (p.Ala178Pro) was identified in the four VTE subjects but not in the normal subjects from the family. An inframeshift variant (rs199469469) was also identified in a paediatric subject of the pedigree. Further evaluation of serum PROC activity levels in p.Ala178Pro variants VTE carriers showed significantly lower PROC activity compared to non-carriers. Furthermore, in vitro study showed that the p.Ala178Pro mutant cells had a consistent reduction in concentration of PROC antigen. In conclusions, our study demonstrated the pathogenic variant (p.Ala178Pro) contributed to PROC type I activity deficiency, which may be due to decreased secretion of PROC.
蛋白 C（PROC）基因突变导致PROC 活性缺乏。本研究旨在鉴定中国家族性静脉血栓形成（VTE）的致病性遗传变异，并探讨其功能后果。进行外显子组测序以鉴定抗凝因子的致病性变异。检测血清凝血和抗凝因子活性以评估遗传关联。在 VTE 患者和体外细胞系中进行 PROC 抗原分泌缺陷的功能研究。在四个 VTE 患者中发现了一个罕见的致病性变异（p.Ala178Pro），但在家族中的正常对照中未发现。在该家系的一个儿科患者中还发现了一个移码变异（rs199469469）。进一步评估 p.Ala178Pro 变异 VTE 携带者的血清 PROC 活性水平显示，与非携带者相比，PROC 活性显著降低。此外，体外研究表明，p.Ala178Pro 突变细胞中 PROC 抗原的浓度持续降低。总之，本研究表明，致病性变异（p.Ala178Pro）导致 PROC Ⅰ型活性缺乏，这可能是由于 PROC 分泌减少所致。
