Molecular and genetic mechanisms of factor XIII A subunit deficiency

Factor XIII is a proenzyme for a plasma transglutaminase. Factor XIII in pl asma is a tetramer (A(2)B(2)) held together by noncovalent bonds, and the A subunit contains the active site. Recently, the three-dimensional structur e of the A subunit has been determined by x-ray crystallography. To underst and the structure-function relationships of the factor XIII molecule and it s clinical implications in factor XIII deficiency, we characterized its gen etic defects and closely examined its gene products, including mRNA and pro tein levels. A variety of missense and nonsense mutations (Arg260-Cys, Tyr2 83-Cys, Gly562-Arg) and deletions/insertions with or without out-of-frame s hift/premature termination and splicing abnormalities (4-bp deletion with 4 64Stop, T insertion at the exon IV/intron D boundary with exon IV-skipping, 20-bp deletion at the exon I/intron A boundary) has been identified in cas es demonstrating A subunit deficiency. In some cases, the A subunit mRNA le vels were severely reduced. Their molecular and cellular bases have also be en explored by expression experiments in mammalian cells and by molecular m odeling. In most cases, impaired folding and/or conformational changes of t he mutant A subunits lead to both intra- and extracellular instability, whi ch is responsible for the A subunit deficiency in the patients.