IDENTIFICATION OF A MUTATION IN A GATA BINDING-SITE OF THE PLATELET GLYCOPROTEIN IB-BETA PROMOTER RESULTING IN THE BERNARD-SOULIER SYNDROME

Bernard-Soulier Syndrome (BSS) is a rare congenital bleeding disorder due to absent or decreased expression of the glycoprotein Ib-IX-V (GpI b-IX-V) receptor complex on the platelet surface. To date, only mutati ons in GpIb alpha or GpIX have been reported in patients with BSS. GpI b beta differs from the other proteins in this receptor in that the ge ne is more complex, and an alternative form is expressed in cells of n on-megakaryocytic lineage, including endothelial cells. It appears tha t the megakaryocytic and endothelial cell mRNA species are transcribed from different start sites and have different proximal promoter regio ns. We have identified a patient with ESS who has a deletion on one ch romosome 22, resulting in velocardiofacial syndrome. The GpIb beta gen e has been mapped to this deleted (22q11.2) region of chromosome 22. T he patient has greatly reduced levels of GpIb beta mRNA and no detecta ble platelet GpIb beta protein, suggesting that his BSS results from a mutation in his remaining GpIb beta allele. Sequence analysis reveale d that the coding region of GpIb beta is normal, but the 5'-upstream r egion contains a C to G transversion at base -133 from the transcripti on start site used in megakaryocytes. The mutation changes a GATA cons ensus binding site, disrupts GATA-1 binding to the mutated site, and d ecreases promoter activity by 84%. Thus, in this patient, Bernard-Soul ier syndrome results from a deletion of one copy of GpIb beta and a mu tated GATA binding site in the promoter of the remaining allele, resul ting in decreased promoter function and GpIb beta gene transcription.