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Molecular Mechanisms of Hypo‐ and Afibrinogenemia
Author(s) -
BRENNAN STEPHEN O.,
FELLOWES ANDREW P.,
GEORGE PETER M.
Publication year - 2001
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2001.tb03496.x
Subject(s) - chemistry , point mutation , biochemistry , endoplasmic reticulum , endoplasmic reticulum associated protein degradation , mutation , proteolysis , microbiology and biotechnology , biology , gene , unfolded protein response , enzyme
A bstract : Point mutations responsible for hypo‐ and afibrinogenemia are yielding new insights into amino acid side chains involved in the molecular processing, assembly, secretion, and domain stability of fibrinogen. Reverse phase chromatography, isoelectric focussing, electrospray mass spectrometry, and tryptic peptide mass mapping have shown that chains with heterozygous mutations of γ284 Gly→Arg, Bβ316 Asp→Tyr and γ371 Thr→Ile are absent from plasma fibrinogen. The nonexpression of these mutations appears to result from perturbation of the five‐stranded β sheet of the D domain. We propose that this is due to retention of the variant in the endoplasmic reticulum and that in turn this leads to hypofibrinogenemia. Other mutations effect intracellular proteolysis and chain assembly. For example the mutation, Aα20 Val→Asp, makes the protein a substrate for furin, which removes the first 19 residues of the Aα chain as the mature molecule transits the trans golgi complex. Transient expression of γ153 Cys→Arg chains together with Aα and Bβ chains suggests this mutation might perturb chain assembly, and the incorporation of mutations of Bβ353 Leu→Arg or Bβ400 Gly→Asp into intracellular fibrinogen precludes its subsequent export from host cells expressing fibrinogen genes. The graded severity of the hypo‐ and afibrinogenemias associated with homozygous Aα chain truncations suggest the absolute minimal requirement for molecular assembly is the formation of the C terminal disulfide ring of the coiled coil.