Glanzmann thrombasthenia in a compound heterozygote for the α IIb gene . A novel missense

Glanzmann thrombasthenia is an autosomal recessive bleeding disorder characterized by a life-long hemorrhagic tendency and absent or severely reduced platelet aggregation in response to agonists. The thrombasthenic phenotype is associated with quantitative or qualitative abnormalities in the platelet fibrinogen receptor, the αIIbβ3 integrin or glycoprotein (GP) IIb-IIIa, which can also serve as a platelet receptor for fibronectin, vitronectin and von Willebrand factor. Heterozygous individuals, with 50-60% the normal amount of platelet αIIbβ3, have no abnormalities of platelet function and are clinically asymptomatic. The platelet content of αIIbβ3 is used to categorize the disease into three types: type I, with total absence of platelet αIIbβ3; type II, with < 20% of normal platelet content; and variant Glanzmann thrombasthenia, with a near normal amount of αIIbβ3. A number of mutations, distributed worldwide, have been found to be associated with Glanzmann thrombasthenia including minor or major deletions, insertions, inversions and mostly point mutations. The functional characterization of many of them has provided important information on the assembly, stability and intracellular transport of the complex. Most of the reported single nucleotide substitutions are located in the coding sequence, and they cause missense or nonsense substitutions at the amino acid level, producing either normal-sized non-functional or truncated proteins. Mutations that alter mRNA splicing are frequently nonsense mutations or mutations directly affecting the standard consensus splicing signals, and typically lead to skipping of the neighboring exon. Less commonly, exonic splicing mutations are missense or even silent mutations that generate an ectopic site that is used preferentially, or activate a cryptic splice site. In nonsenseassociated altered splicing, deletion of exons with premature termination codons appears to be mediated, at least in part, by a mechanism in which recognition of the translational reading-frame is involved. Exon skipping is From the Department of Molecular and Cellular Pathophysiology, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain (AJ, DP, PL, CG-M); Laboratory of Hematology, Hospital Universitario La Paz, Madrid, Spain (VJ).