Work

Analysis of the Phenotype and Gene Mutations of Two Families With Combined Mutations of Anticoagulant Protein Genes

Year: 2026

Type: article

Abstract: BACKGROUND: AT and PC are key components of the anticoagulant system. Mutations in their encoding genes, SERPINC1 and PROC, can lead to insufficient protein levels or impaired function, thereby increasing an individual's susceptibility to venous thromboembolism (VTE). In this study, we describe the clinical characteristics and functional effects of compound heterozygous mutations in SERPINC1 and PROC in two pedigrees. METHODS: Anticoagulant protein activity and antigen levels were evaluated in family members. Targeted sequencing was performed using next-generation sequencing (NGS) and CNVplex technology. The identified variants were assessed for evolutionary conservation, pathogenic potential, and their impact on protein structure. Thrombin generation was measured using the calibrated automated thrombogram (CAT) assay. RESULTS: The PC:A and PC:Ag of proband 1 were decreased to 57% and 59.2%, and PC:A of proband 2 was decreased to 68%. The SERPINC1 (OMIM#:613118) and PROC (OMIM#:176860) gene analysis indicated that there were c.400+5G>A and c.883G>A in proband 1, c.811C>T and c.880C>T in proband 2, respectively. These mutation sites are highly conserved across homologous species. Bioinformatics analysis predicts their potential pathogenicity, suggesting that they may alter the three-dimensional structures of both AT and PC proteins, thereby compromising their functional integrity. Thrombin generation assays revealed that two AT mutation carriers exhibited varying degrees of elevated ETP. In the presence of sTM, two PC mutation carriers showed significantly impaired plasma anticoagulant function without a significant reduction in thrombin generation. CONCLUSION: In both pedigrees, we identified two distinct mutations in AT and PC. Dual mutations in SERPINC1 and PROC confer markedly increased VTE susceptibility.

Source: Molecular Genetics & Genomic Medicine

DOI: 10.1002/mgg3.70191

Authors: Yueli Guo, Tingting Shan, Wenjieying Zheng, Chun Zhao, Wanzhong Kong, Xiaojing Zou

Institution: Zhejiang Chinese Medical University

Language: English

Topic: Blood Coagulation and Thrombosis Mechanisms

Subfield: Hematology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,900