The sequence of alpha 1-antitrypsin is in keeping with its role as a tissue scavenger of leukocyte elastase. Two abnormal variants commonly present in Europeans cause a deficiency that predisposes them to a progressive loss of lung elasticity. The nature of the reactive centre helps explain why cigarette smoking greatly accelerates the onset and severity of this degenerative process to give the disease emphysema.

Hereditary systemic amyloidosis caused by fibrinogen A␣-chain gene mutations is an autosomal dominant condition with variable penetrance, usually of late onset, and typically presents with nephropathy leading to renal failure. Amyloid deposits often develop rapidly in transplanted kidneys, and concomitant orthotopic liver transplantation has lately been performed in several patients with the hope of halting amyloid deposition. Fibrinogen is produced in vitro by hepatocytes but also by other human cell types, and although the liver is the source of plasma fibrinogen in vivo in rats, this is not known in humans. Transplantation of livers expressing wildtype fibrinogen into patients with variant fibrinogen amyloidosis provides a unique opportunity to establish the source of human plasma fibrinogen. We therefore characterized plasma fibrinogen A␣-chain allotypes by electrospray ionization mass spectrometry mapping of tryptic digests before and after liver transplantation. Before liver transplantation, fibrinogen amyloidosis patients with the Glu526Val A␣- IntroductionFibrinogen 1 circulates in the plasma at a concentration of 2 g/L to 4 g/L with a half-life of approximately 4 days and is a modest acute-phase reactant, increasing in concentration in response to most forms of tissue injury, infection, or inflammation. The native 340-kDa molecule is a disulfide-bonded homodimer, each protomer composed of 3 nonidentical disulfide cross-linked polypeptide chains (A␣, B␤, and ␥) that are synthesized under the control of 3 genes. Fibrinogen is produced by cultured hepatocytes in vitro, and plasma fibrinogen has been demonstrated in vivo to come from the liver in rats. 2,3 However, in response to inflammatory mediators, expression of mRNA for individual polypeptide chains and their synthesis and/or secretion in vitro has also been described in a variety of nonhepatic cells, including epithelial cells from various different human tissues, granulosa cells, cervical carcinoma cells, and trophoblasts. 1 Extra-hepatic fibrinogen synthesis may be important for tissue repair at local sites of injury, and/or may have a pathogenetic role, but it is not known whether it contributes significantly to either the normal plasma fibrinogen concentration or to increased concentrations in the acute-phase response.Six mutations encoding sequence variation in the C-terminus of the fibrinogen A␣-chain gene are known to cause autosomal dominant hereditary systemic amyloidosis, in which the amyloid fibrils are composed of fragments of the variant polypeptide. [4][5][6][7][8][9][10][11][12][13] Although there may be widespread visceral and occasional neural involvement, the kidneys are affected first, leading inexorably to end-stage renal failure. There is a high incidence of fibrinogen amyloid deposition in renal allografts as well as progression of amyloid deposition elsewhere. 8,10,11 On the presumption that the liver is the source of the amyloidogenic variant fibrinogen, a combined liver and kidney transplant was first performed in 1995, in a...

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 CGG3 TGG mutation at codon 375 of the fibrinogen ␥ chain gene. This novel ␥375 Arg3 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 ␥ 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, ␥375, is located in the ␥D 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. ( Plasma fibrinogen is synthesized in liver hepatocytes, and a signal peptide is cotranslationally cleaved from each chain as it translocates into the rough endoplasmic reticulum (ER). Chain assembly begins at this point with the formation of A␣-␥ and B␤-␥ intermediates, 5 and the acquisition of an additional B␤ or A␣ chain respectively leads to the formation of an [A␣-B␤-␥] half molecule. 6 Dimerization and disulfide bonding completes the assembly process, and further modification in the Golgi network leads to maturation of Nlinked oligosaccharides at positions B␤ 364 and ␥ 52 and the hydroxylation, sulfation, and phosphorylation of other specific side chains. 1 In the Golgi secretory vesicles, a C-terminal propeptide is removed from the A␣ Abbreviations: ER, endoplasmic reticulum; EM, electron microscopy; PBS, phosphate-buffered saline.From the