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Amy Dear, Stephen O. Brennan, Carl-Erik Dempfle, Werner Kirschstein, Peter M. George
Hypofibrinogenaemia associated with a novel heterozygous 289 Ala Val substitution (fibrinogen Dorfen)
The molecular basis of hypofibrinogenaemia was investigated in a 34-year-old woman and her 10-year-old daughter. DNA sequencing revealed a single heterozygous GCCGTC transition in exon 8 of the fibrinogen ?gene in both subjects, predicting a novel 289 AlaVal substitution. Examination of fibrinogen ?chains by electrospray ionization mass spectrometry failed to detect the variant chain in plasma fibrinogen. Further evidence for its non-expression came from tryptic peptide mapping. The mutation predicts a mass increase of 28 Da in peptide T32, but only the normal (M+2H) ion was detected at 1418 m/z in the proposita. Our finding that 289 is an important determinant of plasma fibrinogen levels highlights the role of mutational analysis in defining structurally important regions of the fibrinogen molecule. This case suggests that the highly conserved Ala289 is important in maintaining structure of the a polymerization site via hydrogen bonding to Thr371.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 92, 12/2004
Pages: 1291 - 1295