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Coagulation Factor XIIIA Subunit Missense Mutations Affect Structure and Function at the Various Steps of Factor XIII Action
Author(s) -
Thomas Anne,
Biswas Arijit,
Dodt Johannes,
Philippou Helen,
Hethershaw Emma,
Ensikat Hans Juergen,
Ivaskevicius Vytautas,
Oldenburg Johannes
Publication year - 2016
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23041
Subject(s) - missense mutation , phenotype , biology , genetics , factor xiii , mutation , gene , genotype phenotype distinction , loss function , factor xiii deficiency , heterozygote advantage , genotype , immunology , fibrin
Inherited defects of coagulation Factor XIII (FXIII) can be categorized into severe and mild forms based on their genotype and phenotype. Heterozygous mutations occurring in F13A1 and F13B genes causing mild FXIII deficiency have been reported only in the last few years primarily because the mild FXIII deficiency patients are often asymptomatic unless exposed to some kind of a physical trauma. However, unlike mutations causing severe FXIII deficiency, many of these mutations have not been comprehensively characterized based on expression studies. In our current article, we have transiently expressed 16 previously reported missense mutations detected in the F13A1 gene of patients with mild FXIII deficiency and analyzed their respective expression phenotype. Complimentary to expression analysis, we have used in silico analysis to understand and explain some of the in vitro findings. The expression phenotype has been evaluated with a number of expression phenotype determining assays. We observe that the mutations influence different aspects of FXIII function and can be functionally categorized on the basis of their expression phenotype. We identified mutations which even in heterozygous form would have strong impact on the functional status of the protein (namely mutations p.Arg716Gly , p.Arg704Gln , p.Gln602Lys , p.Leu530Pro , p.His343Tyr , p.Pro290Arg , and p.Arg172Gln ).