A frequent, apparently silent, polymorphism in prekallikrein (Fletcher factor) gene

Abstract number: P1194

Lombardi^* A., Cabrio^* L., Granzotto^* M., Sartori^* M. T., Girolami^* A.

^*Padua University, Italy

Prekallikrein deficiency (Fletcher defect) is a rare coagulation disorder characterised by a severely prolonged PTT with a silent clinical picture. Molecular biology studies are scanty. The plasma gene (KLK3) is composed of 15 exons and 14 introns and is located to chromosome 4q35. The prekallikrein gene has been studied by PCR amplification and DNA sequence analysis performed on an ABI prism sequencer. The promoter region, all the 15 exons and the exon-intron boundaries of KLK3 gene were amplified using specific primers described in literature [1] We have investigated the prekallikrein gene in order to clarify the molecular basis of a family with this defect. The propositus had very low levels of both prekallikrein activity and antigen and was considered to be homozygous. His parents showed slightly decreased levels of prekallikrein and were considered to be heterozygous for the defect. In the search for the molecular defect, we found a A523G (Asp124 > Ser) polymorphism at the homozygous level in the propositus and in his mother, and at the heterozygous level in his father. Because of the discrepancy between clotting and immunological data and the molecular analysis results, in the kindred studied, we have investigated a group of subjects with normal PTT and prekallikrein levels. In this group, the Asp124 > Ser polymorphism, occurred with a aspargine/serine ratio of 1:2.The same polymorphism had been described by D. W. Chung et al. in a (lambda)gt11 library containing human liver cDNA insert, and screening for human plasma prekallikrein showed instead an aspargine/serine ratio of 7:3.The significance of this difference remains to be clarified. In conclusion, the Asp124 > Ser polymorphism is not responsible for the prekallikrein defect, has apparently no clinical significance, and seems to be frequent.

1  Hongrun, Y, et al.Genomics. 2000;69: 225–234.

2  Chung, et al.Biochemistry. 1986; 25: 2410–2417