Summary
New mutations in the β3 integrin subunit have been identified in two unrelated Glanzmann
thrombasthenia patients originating from India and Bangladesh. Both patients had histories
of excessive bleeding and were found to have Glanzmann thrombasthenia based on absent
ADPinduced platelet aggregation. Immunoblotting of platelet lysates of Patient 1 demonstrated
reduced levels of αIIb and an unexpected high Mr β3 band of ∼260,000, with little
or no normal-sized β3. Upon reduction, a weak β3 band of normal Mr was observed. Platelet
lysates of Patient 2 demonstrated undetectable levels of β3. Sequence analyses identified
homozygous mutations in the β3 genes of both patients. Patient 1 had a C506Y missense
mutation resulting in the expression of an unpaired cysteine; we propose that the
Mr ∼260,000 band is a disulfide-bonded β3 dimer. Patient 2 had an insertion mutation
resulting in a frameshift and premature termination. Both mutations affect biogenesis
of platelet αIIbβ3 receptors.
This work was supported in part by grants HL19278 (B.S.C.), AHA Heritage Affiliate,
Ilma F. Kern Foundation in honor of Jonathan Halperin, MD (D.L.F.), The Charles Slaughter
Foundation (D.L.F.), and a fellowship from an Institutional NRSA, NHLBI T32 HL07824-06
(to W.B.M.)
Keywords
Platelets - αIIbβ3 - Glanzmann thrombasthenia