Gene Variants in Two Families with Inherited Coagulation Factor XI Deficiency and Identification of Mutations

Abstract

<b><i>Introduction:</i></b> Mutations in the <i>F11</i> gene can cause factor XI (FXI) deficiency, leading to abnormal coagulation activity and injury-related bleeding tendency. Therefore, identifying <i>F11</i> gene mutations and studying the molecular basis will help us understand the pathogenesis of FXI deficiency. <b><i>Methods:</i></b> Coagulation tests and gene sequencing analysis of all members were performed. FXI wild-type and mutant expression plasmids were constructed and transfected into HEK293FT cells. The FXI protein expression level was evaluated by ELISA and Western blot. <b><i>Results:</i></b> The FXI activity (FXI:C) and FXI antigen (FXI:Ag) of proband-1 were decreased to 2% and 5%, respectively. FXI:C and FXI:Ag of proband-2 were reduced to 15% and 32%, respectively. Four mutations were found in the two unrelated families, including c.536C&#x3e;T (p.T179M), c.1556G&#x3e;A (p.W519*), c.434A&#x3e;G (p.H145R), and c.1325_1325delT (p.L442Cfs*8). In vitro studies in transiently transfected HEK293FT cells demonstrated that p.T179M, p.W519*, and p.L442Cfs*8 mutations significantly lowered the FXI levels in the culture media. The FXI levels in the culture media and cell lysates of p.H145R mutation were similar to the wild type. <b><i>Conclusion:</i></b> Our results confirm that the four mutations in the <i>F11</i> gene are causative in the 2 FXI deficiency families. Moreover, the p.H145R mutation is a cross-reactive material (CRM)-positive phenotype. The other three mutations are CRM-negative phenotypes and lead to FXI protein secretion disorder.