THE MOLECULAR-GENETIC BASIS OF GLANZMANNS-THROMBASTHENIA IN A GYPSY POPULATION IN FRANCE - IDENTIFICATION OF A NEW MUTATION ON THE ALPHA(IIB) GENE

Glanzmann's thrombasthenia is a rare inherited bleeding disorder cause d by a qualitative or quantitative defect of platelet alpha(IIb) beta( 3). We describe here a new mutation that is the molecular genetic basi s of Glanzmann's thrombasthenia in two gypsy families. Our investigati on was focused on the alpha(IIb) gene as a result of biochemical and i mmunologic analysis of patients' platelets showing undetectable alpha( IIb) but residual beta(3) levels. The entire alpha(IIb) cDNA was polym erase chain reaction (PCR) amplified using patients platelet RNA, Sequ ence analysis showed an 8-bp deletion located at the 3' end of exon 15 . This deletion causes a reading-frame shift leading to a premature st op codon and the synthesis of a severely truncated form of alpha(IIb). Genomic DNA study showed a G --> A substitution, the Gypsy mutation, at the splice donor site of intron 15. This mutation results in an abn ormal splicing occurring at an alternative donor site located 8 bp ups tream from the mutation. Based on those results, an allele-specific PC R analysis was developed to allow a rapid identification of the mutati on in patients and potential carriers of the gypsy community. This PCR analysis can also be used for genetic counseling and antenatal diagno sis. (C) 1995 by The American Society of Hematology.