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 caused by a qualitative or quantitative defect of platelet alpha(IIb) beta(3). We describe here a new mutation that is the molecular genetic basis of Glanzmann's thrombasthenia in two gypsy families. Our investigation was focused on the alpha(IIb) gene as a result of biochemical and immunologic analysis of patients' platelets showing undetectable alpha(IIb) but residual beta(3) levels. The entire alpha(IIb) cDNA was polymerase chain reaction (PCR) amplified using patients platelet RNA, Sequence 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 stop 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 abnormal splicing occurring at an alternative donor site located 8 bp upstream from the mutation. Based on those results, an allele-specific PCR analysis was developed to allow a rapid identification of the mutation in patients and potential carriers of the gypsy community. This PCR analysis can also be used for genetic counseling and antenatal diagnosis. (C) 1995 by The American Society of Hematology.