The XLαs mRNA has a second ORF that encodes another protein termed ALEX (for alternative protein encoded by XLαs mRNA), which uses a termination codon located within exon XL and is, therefore, smaller than XLαs (Fig. 3B). In vitro studies have shown that ALEX, which has a predicted molecular mass of 38 kDa, can interact with XLαs [73, 74]. An insertion polymorphism within XLαs mRNA, affecting both proteins, appears to impair this interaction, a finding that has been offered as an explanation as to why some individuals carrying this insertion polymorphism show elevated agonist-induced cAMP accumulation in platelets [74]. However, this increased agonist responsiveness could also result from elevated Gsα levels, which was demonstrated in several individuals who carried the same insertion polymorphism and had increased bleeding tendency [75]. Hence, the significance of XLαs-ALEX interaction on XLαs or Gsα function remains to be clarified. Of note, this alternative ORF also extends in to the XXLαs mRNA, generating a putative N-terminally extended ALEX variant, termed ALEXX [72]; however, there are currently no available experimental data to suggest that this protein actually exists.
