COMPLETE NUCLEOTIDE-SEQUENCE OF THE ANTITHROMBIN GENE - EVIDENCE FOR HOMOLOGOUS RECOMBINATION CAUSING THROMBOPHILIA

Antithrombin is the principle regulator of thrombin and other blood co agulation proteinases. It is a member of the serpin family of proteina se inhibitors, The genomic sequence of the antithrombin locus has been completed, revealing a gene spanning 13 477 base pairs from the trans cription start site to the poly(A) addition signal. Nine complete and one partial Alu repeat elements were identified within the introns of the gene, with all but one orientated in the reverse direction. Inheri ted deficiency of antithrombin is associated with a venous thrombotic tendency. Restriction fragment mapping of the antithrombin genes in an individual with type I antithrombin deficiency identified an intragen ic deletion in one allele. Localization of the deletion breakpoints in volved restriction analysis and direct sequencing of amplified DNA spa nning the deletion site. The deletion removed 2761 base pairs, affecti ng exon 5 and flanking introns, with the deletion ends contained withi n the left components of two Alu elements. It is likely, therefore, th at the deletion arose by homologous recombination between the two Alu elements.