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Mutations causing coagulation factor XIII subunit A deficiency:
characterization of the mutant proteins after expression in yeast
M Coggan, R Baker, K Miloszewski, G Woodfield and P Board
John Curtin School of Medical Research, Australian National University,
Canberra.
We identified the mutations causing factor XIII A subunit deficiency in two
families. Two distinct mutations were identified in the S family: the
nonsense mutation Tyr 441-->stop in exon 11, inherited through the
paternal line, and the missense mutation Asn 60-->Lys in exon 3,
inherited through the maternal line. Two members of the J family were
heterozygous for the previously described type 3 A subunit. The
substitution giving rise to the type 3 variant was found to be Gly 501--
>Arg in exon 12. The Asn 60-->Lys and Gly 501-->Arg mutations were
constructed in cDNA clones and expressed in yeast (Saccharomyces cerevisiae
AH22). Although mRNA could be detected, protein containing the Asn
60-->Lys substitution could not be detected, suggesting extreme
instability or susceptibility to proteolysis. A subunits containing the Gly
501-->Arg substitution were expressed and found to be enzymatically
active in fresh yeast lysates. This variant has thermal instability and
lost activity during storage or purification. Gel filtration studies
suggested that the type 3 variant assembled as a dimer, as do normal A
subunits. The data suggest that the Gly 501-->Arg (Type 3 variant) would
cause severe factor XIII deficiency if inherited in the homozygous form or
as a compound heterozygote with another deleterious mutation.
Volume 85,
Issue 9,
pp. 2455-2460,
05/01/1995
Copyright © 1995 by The American Society of Hematology
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