Benign FGB (148Lys→Asn, and 448Arg→Lys), and novel causative γ211Tyr→His mutation distinguished by time of flight mass spectrometry in a family with hypofibrinogenaemia

Thrombosis and Haemostasis
Stephen O BrennanJames M Faed

Abstract

We describe a novel procedure for the direct analysis of plasma fibrinogen by HPLC time of flight (TOF) mass spectrometry and apply it to the investigation of a family with hypofibrinogenaemia. Electrospray TOF analysis provided much higher resolution than was possible with our previous quadrupole analyser and revealed three different mass changes within the fibrinogen Bβ and γ chains of the family. It also demonstrated the actual hypofibrinogenaemia phenotype was caused by an aberrantγ chain (-23 Da) which was expressed at a diminished ratio of 0.2:1 relative to γ(A) and co-inherited with a second coequally expressed Bβ variant (Bβ(M) /Bβ(A), 1:1). Co-segregation was confirmed by gene analysis that showed the affected father and son had a very rare Bβ148Lys→Arg mutation (-14 Da) inherited together with a unique new γ211Tyr→His mutation (-26 Da). This latter causative substitution occurs at a site that is absolutely conserved across all fibrinogen chains and preserved across all species. TOF analysis also identified a variant Bβ chain (54,186 Da) that was coequally expressed with normal Bβ chains (54,213 Da) in the unaffected mother.

References

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Citations

Jul 15, 2015·Annals of Clinical Biochemistry·Joshua B RyanPeter M George
Aug 18, 2017·Thrombosis and Haemostasis·Stephen O BrennanAndrew D Laurie
Mar 31, 2015·Journal of Thrombosis and Haemostasis : JTH·A CasiniP de Moerloose
Jun 18, 2015·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·Stephen O BrennanAndrew Grigg
Jun 14, 2016·Haemophilia : the Official Journal of the World Federation of Hemophilia·A Casini, P de Moerloose

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