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Molecular mechanism of a mild phenotype in coagulation factor XIII (FXIII)
deficiency: a splicing mutation permitting partial correct splicing of
FXIII A-subunit mRNA
H Mikkola, L Muszbek, E Laiho, M Syrjala, E Hamalainen, G Haramura, T Salmi, L Peltonen and A Palotie
Department of Clinical Chemistry, University of Helsinki, Finland.
Congenital factor XIII (FXIII) deficiency is potentially a severe bleeding
disorder, but in some cases, the symptoms may be fairly mild. In this
study, we have characterized the molecular mechanism of a mild phenotype of
FXIII A-subunit deficiency in a Finnish family with two affected sisters,
one of whom has even had two successful pregnancies without regular
substitution therapy. In the screening tests for FXIII deficiency, no
A-subunit could be detected, but by using more sensitive assays, a minute
amount of functional A-subunit was seen. 3H-putrescine incorporation assay
showed distinct FXIII activity at the level of 0.35% of controls, and also
the fibrin cross-linking pattern in the patients clotted plasma showed
partial gamma-gamma dimerization. In Western blot analysis, a faint band of
full-length FXIII A-subunit was detected in the patients' platelets. The
patients have previously been identified as heterozygotes for the Arg661
--> Stop mutation. Here we report a T --> C transition at position +6
of intron C in their other allele. The transition affected splicing of
FXIII mRNA resulting in low steady state levels of several variant mRNA
transcripts. One transcript contained sequences of intron C, whereas two
transcripts resulted from skipping of one or two exons. Additionally,
correctly spliced mRNA lacking the Arg661 --> Stop mutation of the
maternal allele could be detected. These results demonstrate that a
mutation in splice donor site of intron C can result in several variant
mRNA transcripts and even permit partial correct splicing of FXIII mRNA.
Further, even the minute amount of correctly processed mRNA is sufficient
for producing protein capable of gamma-gamma dimerization of fibrin. This
is a rare example of an inherited functional human disorder in which a
mutation affecting splicing still permits some correct splicing to occur
and this has a beneficial effect to the phenotype of the patients.
Volume 89,
Issue 4,
pp. 1279-1287,
02/15/1997
Copyright © 1997 by The American Society of Hematology
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