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Fibrinogen Lincoln: a new truncated α chain variant with delayed clotting
Author(s) -
Ridgway Hayley J.,
Brennan Stephen O.,
Gibbons Stephen,
George Peter M.
Publication year - 1996
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.1996.4681007.x
Subject(s) - frameshift mutation , microbiology and biotechnology , amino acid , exon , genetics , gene , fibrinogen , thrombin , stop codon , single strand conformation polymorphism , chemistry , biology , biochemistry , platelet , immunology
A patient referred for preoperative investigation of prolonged bleeding and easy bruising was found to have increased thrombin and reptilase times; however, the thrombin catalysed release of fibrinopeptides A and B was normal. Analysis of five other family members, spanning three generations, indicated that three had a similar defect and suggested autosomal dominant inheritance. Non‐reducing SDS‐PAGE of purified fibrinogen from affected individuals showed that the 340 kD form of their fibrinogen ran as a doublet. SSCP (single‐stranded conformational polymorphism) analysis of exon 5 of the Aα gene, which encodes the C‐terminal half of the chain, confirmed the presence of a mutation. Cycle sequencing of PCR amplified DNA revealed a 13 base pair deletion (nt 4758–4770), resulting in a frameshift at Ala 475, which translates as four new amino acids before terminating at a new stop codon (‐ 476 His‐Cys‐Leu‐Ala‐Stop). The presence of a circulating truncated Aα chain was confirmed when SDS‐PAGE gels were probed with an α chain specific antisera; which showed that the variant Aα chain comigrated with γ chains. The truncation results in a variant Aα chain with a deletion of 131 amino acids (480–610), and four new amino acids at the C‐terminal.