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 (GpIb-IX-V) receptor complex on the platelet surface. To date, only mutations in GpIb alpha or GpIX have been reported in patients with BSS. GpIb beta differs from the other proteins in this receptor in that the gene is more complex, and an alternative form is expressed in cells of non-megakaryocytic lineage, including endothelial cells. It appears that the megakaryocytic and endothelial cell mRNA species are transcribed from different start sites and have different proximal promoter regions. We have identified a patient with ESS who has a deletion on one chromosome 22, resulting in velocardiofacial syndrome. The GpIb beta gene has been mapped to this deleted (22q11.2) region of chromosome 22. The patient has greatly reduced levels of GpIb beta mRNA and no detectable platelet GpIb beta protein, suggesting that his BSS results from a mutation in his remaining GpIb beta allele. Sequence analysis revealed that the coding region of GpIb beta is normal, but the 5'-upstream region contains a C to G transversion at base -133 from the transcription start site used in megakaryocytes. The mutation changes a GATA consensus binding site, disrupts GATA-1 binding to the mutated site, and decreases promoter activity by 84%. Thus, in this patient, Bernard-Soulier syndrome results from a deletion of one copy of GpIb beta and a mutated GATA binding site in the promoter of the remaining allele, resulting in decreased promoter function and GpIb beta gene transcription.