CpG dinucleotides are "hotspots" for mutation in the antithrombin III gene. Twelve variants identified using the...

CpG dinucleotides have been implicated as mutational hotspots in genes that are subject to control mechanisms involving methylation. We have used the polymerase chain reaction to amplify exons 2 and 6 of the human antithrombin III gene and direct sequencing to identify the base replacement in 12 genetic variants. These occurred in individuals with a history of thromboembolic disease due to functional abnormalities of circulating antithrombin: ten had decreased heparin binding and activation, two had decreased inhibitory activity. The amino acid abnormality in ten out of 12 cases had arisen at a CpG dinucleotide; this confirms the CpG sequence as a "hotspot" in the antithrombin gene and explains the observed frequency of occurrence of the same variant antithrombins in diverse populations.