A frameshift mutation in the human fibrinogen Aα-chain gene (Aα[499]Ala frameshift stop) leading to dysfibrinogen San Giovanni Rotondo

M. Margaglione, G. Vecchione, R. Santacroce, F. D'Angelo, B. Casetta, M. L. Papa, E. Grandone, G. Di Minno

Research output: Contribution to journalArticlepeer-review

Abstract

We have investigated a 53-yr-old asymptomatic white man with decreased functional, but not immunologic, fibrinogen plasma levels together with prolonged thrombin and reptilase times, detected through routine coagulation studies prior to a surgical procedure. A new heterozygous single nucleoside deletion (C) at position Ala499 within the Aα-chain gene was identified, which predicted changes of the corresponding aminoacids encoded by the subsequent portion of the exon V and the appearance of a premature stop codon at position 518 (Aα[499]Ala frameshift stop). The new dysfunctional fibrinogen, San Giovanni Rotondo variant, was confirmed in vivo by SDS-PAGE analysis of HPLC-purified fibrinogen chains. Mass spectrum examination of the abnormal HPLC-purified peak gave an estimated mass (56,088 Da) similar to that predicted by DNA analysis of the mutated Aα-chain gene (56,088 Da) and, after tryptic digestion, the truncated Aα-chain was shown only in the propositus, which also carried normal Aα-chain. In addition, mass spectrum analysis of the tryptic digest of the abnormal chain confirmed the presence of a new and unpaired cysteine at the last position that was predicted to form a disulfide bridge with human serum albumin. Immuno-blot analysis confirmed that fibrinogen San Giovanni Rotondo variant, but not normal fibrinogen, contained substantial amounts of albumin. Present findings confirm that truncated Aα-chain lacking part of the terminal domain may be incorporated into mature fibrinogen molecules and normally secreted in the bloodstream.

Original languageEnglish
Pages (from-to)1483-1488
Number of pages6
JournalThrombosis and Haemostasis
Volume86
Issue number6
Publication statusPublished - 2001

Keywords

  • Dysfibrinogenemia
  • Fibrinogen genes
  • Mass spectrometry
  • Truncated protein

ASJC Scopus subject areas

  • Hematology

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