To study structural variants of human serum amyloid A (SAA), an apoprotein of high-density lipoprotein, complementary DNA clones were isolated from a human liver library with the use of two synthetic oligonucleotide mixtures containing sequences that could code for residues 33-38 and 90-95 of the protein sequence. The SAA-specific cDNA clone (pA1) contains the nucleotide sequence coding for the mature SAA and 10 amino acids of the 18-residue signal peptide. It also includes a 70 nucleotide long 3'-untranslated region and approximately 120 bases of the poly(A) tail. The derived amino acid sequence of pA1 is identical with the alpha form of apoSAA1. A fragment of pA1 containing the conserved (residues 33-38) region of SAA also hybridized with RNA from human acute phase liver and acute phase stimulated, but not unstimulated, mouse and rabbit liver. In contrast, a fragment corresponding to the variable region hybridized to a much greater extent with human than with rabbit or murine RNA. Human acute phase liver SAA mRNA (approximately 600 nucleotides in length) directs synthesis of preSAA (Mr 14 000) in a cell-free translating system. In a Xenopus oocyte translation system preSAA is synthesized and processed to the mature Mr 12 000 product. The complete 18 amino acid signal peptide sequence of preSAA was derived from sequencing cDNA synthesized by "primer extension" from the region of SAA mRNA corresponding to the amino terminus of the mature product. Two other SAA-specific cDNA clones (pA6 and pA10) differed from pA1 in that they lack the internal PstI restriction enzyme site spanning residues 54-56 of pA1.(ABSTRACT TRUNCATED AT 250 WORDS)
"The serum amyloid protein (SAA) is an acute phase protein which serum level increases considerably during inflammation and leads, by proteolytic cleavage, to amyloid A proteins, the major fibrillar proteins in secondary amyloidosis . Two isotypes, SAA1 and SAA2, with quite homologous sequences have been distinguished, and allelic forms of these isotypes have been identified . The SAA1 allelic forms have been associated with the incidence of amyloidosis in different diseases and various populations. "
[Show abstract][Hide abstract] ABSTRACT: Familial mediterranean fever (FMF) is a recessively inherited disease characterized by recurrent crises of fever, abdominal, articular and/or thoracic pain. The most severe complication is the development of renal amyloidosis. Over 35 mutations have been discovered so far in the gene responsible for the disease, MEFV. This article aims at determining a correlation between the MEFV genotype and the occurrence of amyloidosis in FMF patients, in addition to the study of the modifying effects of the SAA1 (type 1 serum amyloid A protein) and MICA (Major Histocompatibility Complex (MHC) class-I-chain-related gene A) genes on this severe complication.
Fourteen MEFV mutations were screened and the SAA1 and MICA polymorphisms tested in 30 FMF patients with amyloidosis and 40 FMF patients without amyloidosis.
The M694V and V726A allelic frequencies were, respectively, significantly higher and lower in the group with amyloidosis, compared to the control FMF group. The beta and gamma SAA1 alleles were more frequently encountered in the group without amyloidosis, whereas the alpha allele was significantly more observed in FMF patients with amyloidosis (p < 0.025). All the MICA alleles were encountered in both patients' groups, but none of them was significantly associated with amyloidosis.
The results suggest a protective effect of the SAA1 beta and gamma alleles on the development of amyloidosis and show the absence of a MICA modifying effect on amyloidosis development. Testing these polymorphisms on a larger sample will lead to more definite conclusions.
BMC Medical Genetics 02/2004; 5(1):4. DOI:10.1186/1471-2350-5-4 · 2.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Σε αυτή τη μελέτη εξατάσαμε κατά πόσον οι φλεγμονώδεις κυτοκίνες ρυθμίζουν την έκφραση της δισακχαριδάσης της ψηκτροειδούς παρυφής των εντεροκυττάρων, σουκράσης-ισομαλτάσης(ΣΙ), στην κυτταρική σειρά Caco2. Επίσης εξετάσαμε την πιθανότητα οι κυτοκίνες να ρυθμίζουν την έκφραση και άλλων ειδικών πρωτεϊνών των εντεροκυττάρων, χρησιμοποιώντας την λακτάση σαν πρότυπο. Τέλος εξετάσαμε την πιθανότητα καταστολής του γονιδίου της ΣΙ στα εντεροκύτταρα των λαχνών in vivo, κατά την τοπική φλεγμονώδη αντίδραση της νόσου του Crohn. Για τις μελέτες μας χρησιμοποιήσαμε τεχνικές κυτταροκαλλέργειας, βιοσυνθετικής σήμανσης-ανοσοκαθίζησης-ηλεκτροφόρησης, ανάλυση προστασίας ριβονουκλεάσης, ανοσοϊστοχημεία και ανάλυση υβριδισμού in situ. Τα αποτελέσματα δείχνουν ότι η IL-6 και η IFN-γ προκαλούν ελάττωση, και ο TNFα αύξηση της ΣΙ στα Caco2 κύτταρα. Η σύνθεση τηε λακτάσης δεν επηρεάζεται. Υπάρχει μια εκσεσημασμένη και ειδική ελάττωση της γονιδιακής έκφρασης της ΣΙ στα εντεροκύτταρα των λαχνών ειλεού νόσου του Crohn με οξεία φλεγμονή, σε σύγκριση με παρακείμενο μη φλεγμαίνοντα ειλεό και με φυσιολογικό ειλεό. Τα αποτελέσματα παρέχουν απόδειξη για ένα μέχρι τώρα άγνωστο μηχανισμό ανεπάρκειας δισακχαριδάσης στην εντερική φλεγμονή. In the present study we examined whether inflammatory cytokines regulate the expression of the enterocyte brush border disaccharidase sucrase-isomaltase(SI), in the Caco2 cell line. We also examined the possibility that inflammatory cytokines regulate the expression of other enterocyte-specific proteins, using lactase as a prototype. Last we examined the possibility that SI gene expression is down-regulated in villous enterocytes in vivo during the local inflammatory response of Crohn´s disease. For our studies we used techniques including cell culture, biosynthetic labeling-immunoprecipitation-electrophoresis, ribonuclease protection assay, immunocytochemistry and in situ hybridization anlysis. The results show that IL-6 and IFN-γ mediate a decrease, whereas TNFα mediates an incrase in SI synthesis in Caco2 cells. Synthesis of lactase is not affected. There is a marked and specific decrease in SI gene expression in villous enterocytes in acutely inflammed Crohn´s ileum, as compared to adjacent uninflammed ileum and normal ileum. The results provide evidence for a previously unrecognized mechanism for disaccharidase deficiency in intestinal inflammation.
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