A novel factor XI missense mutation (Val371Ile) in the activation loop is responsible for a case of mild type II factor XI deficiency

Abstract

Coagulation factor XI (FXI) is the precursor of a trypsin-like serine protease that catalyzes, upon activation, the conversion of factor IX (FIX) to activated FIX (FIXa) [1,2]. Human FXI, primarily produced by hepatocytes, is a glycoprotein of 160 kDa circulating in plasma in a noncovalent complex with high molecular mass kininogen [3]. Structurally, FXI zymogen comprises four N-terminal tandem repeats of about 90 residues, named apple domains (Ap1-4), followed by a catalytic serine protease domain located at the C-terminal end. Uniquely among coagulation serine proteases, FXI is secreted as a homodimer composed of two identical polypeptide chains linked by noncovalent interactions and by a Cys321-Cys321 disulfide bond between the Ap4 domains [4,5].Among serine proteases that can activate FXI, i.e. activated factor XII (FXIIa), FXIa, and thrombin, the main physiologic activator is actually thrombin formed on the surface of activated platelets [6][7][8]. Cleavage at the Arg369-Ile370 bond in each monomer produces both an N-terminal heavy chain, which binds FIX and high molecular mass kininogen [9], and a C-terminal Coagulation factor XI (FXI) is the zymogen of a serine protease that, when converted to its active form, contributes to blood coagulation through proteolytic activation of factor IX. FXI deficiency is typically an autosomal recessive disorder, characterized by bleeding symptoms mainly associated with injury or surgery. Of the more than 100 FXI gene mutations reported in FXI-deficient patients, most are associated with a proportional decrease in FXI functional and immunologic levels (type I defects), whereas only a few mutations leading to the presence of dysfunctional molecules in plasma have been molecularly analyzed to date (type II deficiencies). We report the functional and molecular characterization of a missense mutation (Val371Ile) identified, in the heterozygous state, in a 25-year-old Italian male with mild FXI deficiency. Laboratory analysis revealed reduced functional FXI levels (34%), but normal antigen levels (102%), distinctive of a type II defect. Given the proximity of Val371 to the FXI activation site, a possible interference with zymogen activation was postulated. Expression experiments of the FXI-Val371Ile recombinant protein, followed by activation assays, showed both a different time course in FXI activation and a slight delay in factor IX activation by thrombinactivated FXI.

Molecular characterization of two novel mutations causing factor XI deficiency: A splicing defect and a missense mutation responsible for a CRM+ defect

“…In contrasttohaemophilia Aand Band vonWillebrand disease,for which manydysfunctionaldefects have been described (42), fewFXI mutationsare associated with lowactivityand disproportionately high circulatingl evels of FXIa ntigen( CRM+ defects). So far, onlyseven CRM+mutations have been reported; among them, five areclustered in the catalytic domain (Val371Ile [43],A rg378Cys [17], Pro520Leu [44], Gly555Glu [ 45], and Thr575Met [25,46]), which reflects the functional significance of thisdomain in the activityofFXI;and the remaining twomutations arelocated in apple domains (Gly155Glu in A2 [47,48], andS er248Asni nA 3, [49]), suggesting that structuralp erturbation of these domains mayalsoimpair FXI functional activity.…”

Congenital Factor XI Deficiency: An Update

“…Only 11 missense and 1 nonsense mutations have been reported to cause CRMþ deficiency. 1,8,18,[70][71][72][73][74][75][76][77][78][79] Even though point mutations represent the vast majority of identified defects (98%), large deletions do exist. 8,80,81 The actual number of mutations remains unknown because of difficulties in publishing studies identifying mutations without functional expression studies.…”

Factor XI Deficiency

“…Among missense defects, only seven mutations leading to CRM þ deficiency have been reported. 7,[63][64][65][66][67][68] Even though point mutations represent the vast majority of identified mutations, large deletions do exist (see Fig. 1).…”