In this study we have assumed that finding a mutant protein within the RER of a given cell, is a proof of primary synthesis in analogy with the presence of a given protein in a monolayer medium-free cell culture, although the final proof would be the demonstration of functioning mRNA in that cell. Gene expression of AAT has been demonstrated in human monocytes/macrophages in both Pi MM normal phenotypes and AATD [43,44]. a divergent behavior in export. Moreover, 100% of the M fraction, but only 15% of the Z, are secreted into the blood. That results in an elevation of serum AAT levels up to the normal range associated with an increase of the amount of hepatic storage. The phenomenon has been called Recruitment-Secretory Block (R-SB) and explains why heterozygous Pi MZ individuals are not prone to develop the extrahepatic manifestations observed in Pi ZZ homozygotes as a consequence of the severe serum AAT deficiency. HHHS occurs only in the heterozygous state. The R-SB phenomenon neither apply to homozygous Pi ZZ nor to heterozygous HHHS individuals, thus suggesting that this homozygosity of HHHS could be incompatible with life. In contrast to fibrinogen that is synthesized exclusively and selectively by the liver, AAT can be synthesized by various tissues and cell types, a.o. macrophages, bile duct, pancreatic islet and sperm cells. Simultaneous accumulation of AAT in the RER of both hepatocytes and these cell types, indicates a mutation and a primary synthesis. Cells other than hepatocytes do not respond to acute phase stimuli and do not contribute to SJ 172550 the circulating levels. Indeed, Pi ZZ cirrhotic patients, after liver transplantation from a Pi MM donor, acquire permanently the donors phenotype and correct the serum AAT deficiency. Based on morphological, physiological, and serological correlations, it is suggested that AAT in cells other than hepatocyte is packaged in condensing vacuoles, lysosomes, and endocrine granules in the form of proteaseCantiprotease complexes and is playing an intracellular role. The liver is the only source of fibrinogen. Therefore, the mutations causing conformational molecule abnormalities, result in exclusive hepatic storage. The storage of mutant AAT and fibrinogen is usually toxic for the hepatocytes and causes chronic liver disease and cirrhosis. Molecular analyses of the storing mutations and 3D modeling studies have localized the mutations in critical sites for correct assembly and secretion and have clarified the pathomorphogenesis of the aggregation process of the proteins within the RER. In this article, we review clinical and experimental published data collected over 40 years. Taken together, the results appear to be of potential utility with regard to therapeutic strategies aimed to cure ERSD. In particular, they discourage the use of drugs that would increase the synthesis without a SJ 172550 simultaneous increase of secretion. This article also addresses future research directed at small molecules that can prevent intracellular accumulation and increase the degradation SJ 172550 of the mutant proteins. 1. Rabbit Polyclonal to OR2AG1/2 Introduction Endoplasmic reticulum storage diseases (ERSD) are genetic disorders affecting secretory proteins. Due to mutations in the encoding genes, the proteins may acquire an abnormal conformation of the molecule that aggregates within the rough endoplasmic reticulum (RER) instead of being regularly exported . The process results in plasma deficiency and intracellular storage. The storage in turn causes chronic liver disease and cirrhosis. The prototype of ERSD is usually alpha-1-antitrypsin deficiency (AATD). Its discovery represents a milestone in the medical field as it has led to clarify the pathogenesis of a subset of liver cirrhosis previously considered cryptogenic . It has also clarified the pathogenesis of pulmonary emphysema in AATD  and that of emphysema in general [4,5]. The original recognition of AATD patients was done on the basis of identification on serum isoelectric focusing (IF) on polyacrylamide gel  of a variant of AAT called Z because of the slowest migration velocity as compared to all other variants. The Z AAT was subsequently found to carry.