Hypofibrinogenaemia associated with a novel heterozygous γ289 Ala→Val substitution (fibrinogen Dorfen)

Abstract

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 GCC-->GTC transition in exon 8 of the fibrinogen gamma ?gene in both subjects, predicting a novel gamma289 Ala-->Val substitution. Examination of fibrinogen gamma ?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 gamma289 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 Ala(289) is important in maintaining structure of the "a" polymerization site via hydrogen bonding to Thr(371).