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Splice site mutation in the human protein C gene associated with venous
thrombosis: demonstration of exon skipping by ectopic transcript analysis
B Lind, WW van Solinge, M Schwartz and S Thorsen
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.
Heterozygosity for a G-->C mutation converting the highly conserved
Gln184 (CAG) to His (CAC) was identified at the last nucleotide of exon 7
of the protein C gene in two family members with deep vein thrombosis. As
the nucleotide is a part of the 5 splice site of intron G, it was examined
how the mutation affected splicing of protein C pre- mRNA. Relevant protein
C cDNA fragments were amplified with polymerase chain reaction after
reverse transcription of ectopic mRNA from peripheral blood lymphocytes.
Southern blot analysis and nucleotide sequencing of these fragments showed
a fragment (A) corresponding to correctly spliced mRNA originating from the
normal allele and a fragment (B) corresponding to a truncated mRNA lacking
exon 7, originating from the mutant allele. A third fragment (C) lacking
exons 7 and 8 was identified in both affected and unaffected family
members, as well as in normal controls. Analysis of human liver protein C
mRNA indicated that the ectopic lymphocyte mRNA was qualitatively
representative for the tissue-specific mRNA. In conclusion, evidence is
provided showing that the mutation abolishes formation of correctly spliced
mRNA. This agrees with the observation that the mutation results in a type
1 protein C deficiency.
Volume 82,
Issue 8,
pp. 2423-2432,
10/15/1993
Copyright © 1993 by The American Society of Hematology
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