A Study on the Molecular Mechanism for Hereditary Type II Antithrombin Deficiency in a Chinese Pedigree.

Objective: To identify the phenotype and study for the genetic mechanism underlying the recurrence of deep vein thrombosis formation in members of a Chinese pedigree caused by antithrombin (AT) deficiency.

Methods: AT antigen level (AT:Ag) and AT activity (AT:A) were detected with respectively immuno-nephelometry and chromogenic assay. All the seven exons and the flank regions of AT gene form the propositus were amplified by PCR. The purified PCR products were sequenced directly. After mutation was found, the corresponding gene fragments covering the mutated point from the other members of the pedigree were amplified and sequenced.

Results: The plasma level of AT:Ag of the propositus was 29.80mg/dl and those of other 3 members of the kindred ranged from 30.90 to 34.00mg/dl, all were among normal range. The AT:A of the propositus was 56%, and those of the other members were 62% to 68%, all were lower than normal. A heterozygous G13830A missense mutation in exon 6 was identified, which has led to the substitution of histamine (CAT) 393 for arginine (CGT). The sequencing results from the pedigree suggested that all the three other members of the kindred also had the same heterozygous mutation.

Conclusion: The R393H mutation in AT which is similar to the AT Glasgow and AT Avranches can cause reactive site injury in AT so that it is not able to inhibit thrombin anymore. The gene mutation found in this pedigree which was unreported in China is the molecular mechanism for recurrent thrombosis events in two members of the kindred.