RESUMEN
Glanzmann thrombasthenia is an inherited bleeding disorder arising from quantitative or qualitative defects of the alphaIIbbeta3 integrin of platelets. Here, we report that PCR-SSCP analysis and DNA sequencing revealed a homozygous single base pair substitution in exon 12 of the IIb gene leading to a Glu(324) (E) to Lys (K) substitution in the alphaIIb subunit in a patient with Type I disease. As this mutation is found on at least 3 continents, the codon for Glu(324) may be a mutational hotspot of the disease. To better understand this mutation, we analyzed the effect of substituting E(324) with A(324), L(324), D(324), Q(324), N(324), S(324), as well as K(324), looking at both alphaIIbbeta3 maturation and cell surface expression in transiently transfected Cos-7 cells. The maturation state of the receptor clearly correlated with the level of cell membrane expression. Maturation efficiency was dependent on the electric charge as well as the size of the side chain of the amino acid present in what is a highly conserved N-terminal position in the third beta-strand of blade 5 of the alphaIIbeta beta-propeller.