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Glanzmann Thrombasthenia. Cooperation Between Sequence Variants In Cis During Splice Site Selection., Ying Jin, Harry C. Dietz, Robert A. Montgomery, William R. Bell, Iain Mcintosh, Barry Coller, Paul F. Bray

Cardeza Foundation for Hematologic Research

Glanzmann thrombasthenia (GT), an autosomal recessive bleeding disorder, results from abnormalities in the platelet fibrinogen receptor, GP(IIb)-IIIa (integrin alpha(IIb)beta3). A patient with GT was identified as homozygous for a G-->A mutation 6 bp upstream of the GP(IIIa) exon 9 splice donor site. Patient platelet GP(IIIa) transcripts lacked exon 9 despite normal DNA sequence in all of the cis-acting sequences known to regulate splice site selection. In vitro analysis of transcripts generated from mini-gene constructs demonstrated that exon skipping occurred only when the G-->A mutation was cis to a polymorphism 116 bp upstream, providing precedence that two sequence variations …