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Thromb Haemost 1998; 79(06): 1086-1091
DOI: 10.1055/s-0037-1615020
Rapid Communication
Schattauer GmbH

A Novel Mutation in Intron K of the PROS1 Gene Causes Aberrant RNA Splicing and Is a Common Cause of Protein S Deficiency in a UK Thrombophilia Cohort

N. J. Beauchamp
1   From the Division of Molecular and Genetic Medicine, Royal Hallamshire Hospital, Sheffield, UK
,
M. E. Daly
1   From the Division of Molecular and Genetic Medicine, Royal Hallamshire Hospital, Sheffield, UK
,
M. Makris
1   From the Division of Molecular and Genetic Medicine, Royal Hallamshire Hospital, Sheffield, UK
,
F. E. Preston
1   From the Division of Molecular and Genetic Medicine, Royal Hallamshire Hospital, Sheffield, UK
,
I. R. Peake
1   From the Division of Molecular and Genetic Medicine, Royal Hallamshire Hospital, Sheffield, UK
› Author AffiliationsSupported by a grant from the British Heart Foundation.
Further Information

Publication History

Received 10 October 1997

Accepted after resubmission 04 February 1998

Publication Date:
07 December 2017 (online)

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Summary

In the course of investigating the molecular basis of protein S deficiency in 31 index cases with thrombophilia, we identified seven kindred where the underlying defect was a novel A to G transition 9 bp upstream of exon 12 in intron K of the PROS1 gene. In all but one case, the mutation caused type I deficiency. One individual had type III deficiency. While ectopic transcript analysis using the BstXI dimorphism in exon 15 failed to detect a transcript from the mutated allele, analysis of transcripts spanning exons 11 and 12 revealed a minor mRNA species. Sequencing confirmed the mutation created a new RNA acceptor site introducing 8 nucleotides of intronic sequence into the mature mRNA. Haplotype analysis of the defective PROS1 alleles in six families revealed the same haplotype in all affected individuals suggesting the presence of a common ancestor. Six of the fourteen relatives with the mutation experienced at least one venous thrombotic event strongly supporting the association of the mutation with venous thrombosis.

 

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