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

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


Glanzmann thrombasthenia (GT), an autosomal recessive bleeding disorder, results from abnormalities in the platelet fibrinogen receptor, GPIIb-IIIa (integrin α(IIb)β3). A patient with GT was identified as homozygous for a G→A mutation 6 bp upstream of the GPIIIa exon 9 splice donor site. Patient platelet GPIIIa 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 in the same exon which do not alter consensus splice sites and do not generate missense or nonsense mutations, can affect splice site selection. The mutant transcript resulted from utilization of a cryptic splice acceptor site and returned the open reading frame. These data support the hypothesis that pre- mRNA secondary structure and allelic sequence variants can influence splicing and provide new insight into the regulated control of RNA processing. In addition, haplotype analysis suggested that the patient has two identical copies of chromosome 17. Markers studied on three other chromosomes suggested this finding was not due to consanguinity. The restricted phenotype in this patient may provide information regarding the expression of potentially imprinted genes on chromosome 17.

Original languageEnglish (US)
Pages (from-to)1745-1754
Number of pages10
JournalJournal of Clinical Investigation
Issue number8
StatePublished - Oct 15 1996


  • Glanzmann thrombasthenia
  • RNA splicing
  • exon skipping
  • molecular genetics
  • platelet membrane glycoprotein complex IIb- IIIa

ASJC Scopus subject areas

  • General Medicine


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