Molecular Genetics

The gene for factor XI is located on the distal end of chromosome 4 (4q35).[17] It is 23 kb in size and consists of 15 exons (numbered 1-15) and 14 introns (named A-N).

Exon 1 is not translated and exon 2 codes for a signal peptide of 18-amino acids length, which is not integrated into the final protein.[18] Plasma factor XI is the gene product of exon 3-15 and contains a heavy chain of 369 amino acids and a light chain 238 amino acids in length.[5] Platelet factor XI mRNA was reported to be an alternative splicing product lacking exon 5; however, this was not confirmed by other research groups.[2,19] The heavy chain harbors four tandem repeats of 90-91 amino acids, named apple domains (A1-A4). Each one is encoded by two successive exons starting from exon 3.[5,18] Several binding sites are located within these domains. To a large extent, the implicated amino acids have been elucidated.[20-24] The A1 domain carries a binding site for prothrombin as well as binding sites for HK and thrombin.[3] Binding of prothrombin or HK to the A1 domain results in exposure of a platelet-binding site on the A3 domain.[1,24] The interaction of the A3 domain with activated platelets is mediated through binding to GPIb-IX-V complexes within lipid rafts in the platelet membrane.[25] Moreover, a binding site for unfractionated heparin was localized on the A3 domain.[22] Both the A2[20] and the A3 domain[21] were reported to mediate factor IX activation. On the A4 domain, a binding site for factor XIIa was localized.[23] The A4 domain is also essential for factor XI dimer formation because it mediates initial noncovalent dimerization of two factor XI subunits and harbors the Cys321 residue responsible for subsequent dimer stabilization by a single disulfide bond.[26] The light chain is encoded by exon 11-15.[5,18] It contains the active site formed by the catalytic triad (His413, Asp462, and Ser557)[5] typical for most serine proteases, as well as a high-affinity heparin-binding site.[27]

With the exception of three deletions and three insertions,[14,17,28-30] all published mutations associated with factor XI deficiency involving exon 3-15 are singlebase substitutions, which are mostly missense mutations. Many are located within binding sites. Therefore one may expect aberrant factor XI molecules to circulate and interfere with normal factor XI function. However, in most instances when factor XI activity and antigen were determined, both were simultaneously reduced.[7] In fact, a defect in secretion was demonstrated for a number of factor XI variants expressed in cell lines, indicating that, in general, circulating factor XI in deficient individuals will be composed of normal monomers.[14,31] However, a few cases of circulating dysfunctional factor XI protein have been reported.[6] Recently, two novel variants with normal expression in cell culture systems were described in several patients. One individual with reduced but appreciable factor XI activity and antigen was compound heterozygous for these mutations. Consequently, all circulating factor XI of this individual must only consist of abnormal monomers. Furthermore, in individuals heterozygous for such mutations, the variant molecules may participate in circulating factor XI forming either homodimers or combine to heterodimers together with normal factor XI molecules.[15,16]

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Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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