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Deficiency in the A-subunit of coagulation factor XIII: two novel point
mutations demonstrate different effects on transcript levels
H Mikkola, M Syrjala, V Rasi, E Vahtera, E Hamalainen, L Peltonen and A Palotie
Department of Clinical Chemistry, University of Helsinki, Finland.
Congenital deficiency in coagulation factor XIII is a rare autosomal
recessive bleeding disorder. Although the defect was characterized over 30
years ago, little is known about the molecular basis of the disorder. Here,
we show two novel point mutations in the gene of the A- subunit of factor
XIII in the genetically isolated population of Finland. All eight factor
XIII-deficient families identified in Finland were studied. The exons of
the gene of A-subunit were amplified individually by polymerase chain
reaction and subsequently screened by single-strand conformation
polymorphism. Sequence analysis of the abnormally migrating fragments
showed two point mutations resulting in an amino acid alteration. A C-to-T
transition at Arg-661 in exon XIV created a premature stop codon. This
mutation was detected in six of the eight families, thus being the major
alteration causing FXIII deficiency in Finland. In two of the six families,
the patients were compound heterozygotes with the Arg-661-Stop mutation in
one allele and either a T-to-C point mutation in exon VI or a thus far
uncharacterized mutation in the other allele. The T-to-C transition in exon
VI resulted in a substitution of threonine for methionine 242. The
transition was found in one family only, where it was in the heterozygote
form combined with the Arg-661-Stop mutation. To evaluate the consequences
of these mutations, steady-state FXIII mRNA levels were quantitated by
solid-phase minisequencing. In addition to the termination of translation
70 amino acids before the initial stop codon, the Arg-661- Stop mutation
causes a 10- to 30-fold reduction in FXIII mRNA levels. This is also likely
to result in a low translation level in the truncated polypeptide. In
contrast, Met-242-Thr mutation does not seem to affect the level of mRNA.
Here, the absence of a functional and immunodetectable protein is probably
caused by an altered conformation of the mutant polypeptide, resulting in
early degradation of the defective protein.
Volume 84,
Issue 2,
pp. 517-525,
07/15/1994
Copyright © 1994 by The American Society of Hematology
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