Thromb Haemost 2014; 111(04): 679-684
DOI: 10.1160/TH13-08-0657
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

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

Stephen O. Brennan
1   Molecular Pathology Laboratory, Pathology Department, University of Otago, Christchurch, New Zealand
2   Canterbury Health Laboratories, Christchurch, New Zealand
,
Hilda Mangos
3   Oncology-Haematology Department, Dunedin Public Hospital, New Zealand
,
James M. Faed
3   Oncology-Haematology Department, Dunedin Public Hospital, New Zealand
4   Pathology Department, University of Otago Dunedin, Dunedin, New Zealand
› Author Affiliations
Further Information

Publication History

Received: 11 August 2013

Accepted after major revision: 26 October 2013

Publication Date:
01 December 2017 (online)

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Summary

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 aberrant _ chain (-23 Da) which was expressed at a diminished ratio of 0.2:1 relative to γA and co-inherited with a second coequally expressed Bβ variant (BβM /BβA, 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 B_ chain (54,186 Da) that was coequally expressed with normal Bβ chains (54,213 Da) in the unaffected mother.