Genetic analysis of mutations in seven Japanese families with type I antithrombin deficiency

We have performed genetic analysis on seven Japanese families with type I antithrombin (AT) deficiency by the polymerase chain reaction (PCR)/direct DNA sequencing method. Five distinct mutations including two novel ones were identified in six of seven families. All subjects investigated were heterozygous for the mutations. In one family, however, no genetic abnormality was found within the analyzed DNA sequences. The identified mutations were as follows: (1) a T-to-C substitution at nucleotide position 2747, which predicts an amino acid replacement of Cys (TGT) 95 by Arg, was found in two families; (2) a 4-bp deletion (-TTTC) at nucleotide position 2647-2650, which causes frameshift and a premature stop codon at codon 80; (3) a 3-bp deletion (-CTT) within nucleotide position 5356-64, which causes deletion of a Phe at amino acid numbers 121-123; (4) a C-to-T substitution at nucleotide 5381, which induces a replacement of Arg (CGA)129 by a stop codon (TGA); (5) a C-to-T substitution at nucleotide number 2745, which causes an amino acid replacement of Ala (GCC) 94 by Val (GTC). Our results confirm that the genetic background and molecular pathogenesis of type I AT deficiency is highly heterogeneous.