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Novel fibrinogen γ375 Arg→Trp mutation (fibrinogen aguadilla) causes hepatic endoplasmic reticulum storage and hypofibrinogenemia
Author(s) -
Brennan Stephen O.,
Maghzal Ghassan,
Shneider Benjamin L.,
Gordon Ronald,
Magid Margret S.,
George Peter M.
Publication year - 2002
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2002.35063
Subject(s) - hypofibrinogenemia , endoplasmic reticulum , fibrinogen , microbiology and biotechnology , chemistry , gel electrophoresis , biochemistry , biology
The proposita and her sister had chronically elevated liver function test results, and needle biopsy specimens showed scattered eosinophilic inclusions within the hepatocytes. On immunoperoxidase staining, the inclusions reacted strongly with anti‐fibrinogen antisera; on electron‐microscopic (EM) examination, the material appeared confined to the endoplasmic reticulum (ER) and was densely packed into tubular structures with a swirling fingerprint appearance. Coagulation investigations showed low functional and antigenic fibrinogen concentrations that were indicative of hypofibrinogenemia. Amplification and DNA sequencing showed a heterozygous CGG→TGG mutation at codon 375 of the fibrinogen γ chain gene. This novel γ375 Arg→Trp substitution segregated with hypofibrinogenemia in 3 family members and was absent from 50 normal controls. When purified plasma fibrinogen chains were examined by sodium dodecyl sulfate/polyacrylamide gel electrophoresis, reverse‐phase chromatography, electrospray ionization mass spectrometry, and isoelectric focusing, only normal γ chains were detected. In conclusion, we propose that this nonconservative mutation causes a conformational change in newly synthesized molecules and that this provokes aggregation within the ER and in turn causes the observed hypofibrinogenemia. Whereas the mutation site, γ375, is located in the γD domain at the jaws of the primary E‐to‐D polymerization site, purified plasma fibrinogen showed normal polymerization, supporting our contention that molecules with variant chains never reach the circulation but accumulate in the ER.