Factor XIII deficiency is a rare autosomal recessive bleeding disorder that is characterized by defective crosslinking of fibrin and poor resistance to fibrinolysis. We have characterized seven mutations in FXIII A-subunit gene: Four missense mutations (Met242->Thr. Arg252->Ile, Arg326->Gln and Leu498->Pro) and three nonsense mutations (Arg661->Stop, delT Phe8 and a splicing defect T->C at position +6 in intron C) The expression of FXIII Asubunit was studied in vivo on mRNA and protein level. The structural effects of the mutations were predicted from the three dimensional model of crystallized FXIII A-subunit. (Mikkola et al. Blood 1994, 84:517-525, Mikkola et al. Blood 1996,87:141-151) The missense mutations were further studied by in vitro expression in COS cells. All of them interfere with the enzymatic activity and render the protein susceptible for intracellular degradation. There is considerable phenotypic variation within FXIII deficient patients but little is known about the phenotype-genotype correlation. One of the Finnish patients has an untypically mild phenotype as she has had two succesful pregnancies without FXIII substitutions. She is a compound heterozygote for Arg661->Stop mutation and the splicing mutation (T->C at position +6 of intron C). Analysis of the patients FXIII A-subunit mRNA, antigen and activity in platelets and fibrin cross-linking pattern in plasma suggest partial readthrough of the splicing mutation resulting in a small amount of active enzyme and thus a milder phenotype.
|Number of pages||1|
|Issue number||SUPPL. 3|
|Publication status||Published - Dec 1 1996|
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