Abstract
We have identified a novel 69-kD peptide autoantigen (ICA69) associated with insulin-dependent diabetes mellitus (IDDM) by screening a human islet lambda gt11 cDNA expression library with cytoplasmic islet cell antibody positive sera from relatives of IDDM patients who progressed to the overt disease. The deduced open reading frame of the ICA69 cDNA predicts a 483-amino acid protein. ICA69 shows no nucleotide or amino acid sequence relation to any known sequence in GenBank, except for two short regions of similarity with BSA. The ICA69 cDNA probe hybridizes with a 2-kb mRNA in poly(A+) RNA from human pancreas, brain, heart, thyroid, and kidney, but not with skeletal muscle, placenta, spleen, or ovary. Expression of ICA69 was also detected in beta cells and cell lines, as well as in tumoral tissue of islet cell origin. The native ICA69 molecule migrates to 69 kD in SDS-PAGE as detected with specific antibodies. Serum samples from relatives of IDDM patients specifically reacted with affinity-purified recombinant ICA69 on Western blotting. The structural gene for ICA69 was designated ICA1. A homologue in the mouse, designated Ica-1 was mapped to the proximal end of chromosome 6 (within 6 cM of the Met protooncogene). ICA69 adds a novel autoantigen to the family of identified islet target molecules, and by the manner of its identification and characterization large amounts of antigen are available for development of quantitative, convenient predictive assays for autoantibodies and analysis of the role of this molecule in diabetes autoimmunity, as well as its physiologic function.
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- Amann E., Ochs B., Abel K. J. Tightly regulated tac promoter vectors useful for the expression of unfused and fused proteins in Escherichia coli. Gene. 1988 Sep 30;69(2):301–315. doi: 10.1016/0378-1119(88)90440-4. [DOI] [PubMed] [Google Scholar]
- Baekkeskov S., Aanstoot H. J., Christgau S., Reetz A., Solimena M., Cascalho M., Folli F., Richter-Olesen H., De Camilli P., Camilli P. D. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature. 1990 Sep 13;347(6289):151–156. doi: 10.1038/347151a0. [DOI] [PubMed] [Google Scholar]
- Benedum U. M., Baeuerle P. A., Konecki D. S., Frank R., Powell J., Mallet J., Huttner W. B. The primary structure of bovine chromogranin A: a representative of a class of acidic secretory proteins common to a variety of peptidergic cells. EMBO J. 1986 Jul;5(7):1495–1502. doi: 10.1002/j.1460-2075.1986.tb04388.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bottazzo G. F., Genovese S., Bosi E., Dean B. M., Christie M. R., Bonifacio E. Novel considerations on the antibody/autoantigen system in type I (insulin-dependent) diabetes mellitus. Ann Med. 1991 Oct;23(4):453–461. doi: 10.3109/07853899109148089. [DOI] [PubMed] [Google Scholar]
- Broze G. J., Jr, Miletich J. P. Isolation of the tissue factor inhibitor produced by HepG2 hepatoma cells. Proc Natl Acad Sci U S A. 1987 Apr;84(7):1886–1890. doi: 10.1073/pnas.84.7.1886. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bréant B., Lavergne C., Rosselin G. Cell cycle and gene expression in the insulin producing pancreatic cell line beta TC1. Diabetologia. 1990 Oct;33(10):586–592. doi: 10.1007/BF00400201. [DOI] [PubMed] [Google Scholar]
- Castaño L., Russo E., Zhou L., Lipes M. A., Eisenbarth G. S. Identification and cloning of a granule autoantigen (carboxypeptidase-H) associated with type I diabetes. J Clin Endocrinol Metab. 1991 Dec;73(6):1197–1201. doi: 10.1210/jcem-73-6-1197. [DOI] [PubMed] [Google Scholar]
- Christgau S., Aanstoot H. J., Schierbeck H., Begley K., Tullin S., Hejnaes K., Baekkeskov S. Membrane anchoring of the autoantigen GAD65 to microvesicles in pancreatic beta-cells by palmitoylation in the NH2-terminal domain. J Cell Biol. 1992 Jul;118(2):309–320. doi: 10.1083/jcb.118.2.309. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Clark S. A., Burnham B. L., Chick W. L. Modulation of glucose-induced insulin secretion from a rat clonal beta-cell line. Endocrinology. 1990 Dec;127(6):2779–2788. doi: 10.1210/endo-127-6-2779. [DOI] [PubMed] [Google Scholar]
- Cleveland D. W., Lopata M. A., MacDonald R. J., Cowan N. J., Rutter W. J., Kirschner M. W. Number and evolutionary conservation of alpha- and beta-tubulin and cytoplasmic beta- and gamma-actin genes using specific cloned cDNA probes. Cell. 1980 May;20(1):95–105. doi: 10.1016/0092-8674(80)90238-x. [DOI] [PubMed] [Google Scholar]
- Contreras G., Summers D. F., Maizel J. V., Ehrenfeld E. HeLa cell nucleolar RNA synthesis after poliovirus infection. Virology. 1973 May;53(1):120–129. doi: 10.1016/0042-6822(73)90471-6. [DOI] [PubMed] [Google Scholar]
- Coppel R. L., Gershwin M. E., Sturgess A. D. Cloned autoantigens in the study and diagnosis of autoimmune diseases. Mol Biol Med. 1989 Feb;6(1):27–34. [PubMed] [Google Scholar]
- Dean M., Park M., Le Beau M. M., Robins T. S., Diaz M. O., Rowley J. D., Blair D. G., Vande Woude G. F. The human met oncogene is related to the tyrosine kinase oncogenes. 1985 Nov 28-Dec 4Nature. 318(6044):385–388. doi: 10.1038/318385a0. [DOI] [PubMed] [Google Scholar]
- Dietrich W., Katz H., Lincoln S. E., Shin H. S., Friedman J., Dracopoli N. C., Lander E. S. A genetic map of the mouse suitable for typing intraspecific crosses. Genetics. 1992 Jun;131(2):423–447. doi: 10.1093/genetics/131.2.423. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dotta F., Colman P. G., Lombardi D., Scharp D. W., Andreani D., Pontieri G. M., Di Mario U., Lenti L., Eisenbarth G. S., Nayak R. C. Ganglioside expression in human pancreatic islets. Diabetes. 1989 Nov;38(11):1478–1483. doi: 10.2337/diab.38.11.1478. [DOI] [PubMed] [Google Scholar]
- Dropcho E. J., Chen Y. T., Posner J. B., Old L. J. Cloning of a brain protein identified by autoantibodies from a patient with paraneoplastic cerebellar degeneration. Proc Natl Acad Sci U S A. 1987 Jul;84(13):4552–4556. doi: 10.1073/pnas.84.13.4552. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Eisenbarth G. S. Type I diabetes mellitus. A chronic autoimmune disease. N Engl J Med. 1986 May 22;314(21):1360–1368. doi: 10.1056/NEJM198605223142106. [DOI] [PubMed] [Google Scholar]
- Elliott R. B., Martin J. M. Dietary protein: a trigger of insulin-dependent diabetes in the BB rat? Diabetologia. 1984 Apr;26(4):297–299. doi: 10.1007/BF00283653. [DOI] [PubMed] [Google Scholar]
- Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
- Friedman K. D., Rosen N. L., Newman P. J., Montgomery R. R. Enzymatic amplification of specific cDNA inserts from lambda gt11 libraries. Nucleic Acids Res. 1988 Sep 12;16(17):8718–8718. doi: 10.1093/nar/16.17.8718. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Genovese S., Bonifacio E., McNally J. M., Dean B. M., Wagner R., Bosi E., Gale E. A., Bottazzo G. F. Distinct cytoplasmic islet cell antibodies with different risks for type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1992 Apr;35(4):385–388. doi: 10.1007/BF00401207. [DOI] [PubMed] [Google Scholar]
- Gianani R., Pugliese A., Bonner-Weir S., Shiffrin A. J., Soeldner J. S., Erlich H., Awdeh Z., Alper C. A., Jackson R. A., Eisenbarth G. S. Prognostically significant heterogeneity of cytoplasmic islet cell antibodies in relatives of patients with type I diabetes. Diabetes. 1992 Mar;41(3):347–353. doi: 10.2337/diab.41.3.347. [DOI] [PubMed] [Google Scholar]
- Gillard B. K., Thomas J. W., Nell L. J., Marcus D. M. Antibodies against ganglioside GT3 in the sera of patients with type I diabetes mellitus. J Immunol. 1989 Jun 1;142(11):3826–3832. [PubMed] [Google Scholar]
- Hagopian W. A., Michelsen B., Karlsen A. E., Larsen F., Moody A., Grubin C. E., Rowe R., Petersen J., McEvoy R., Lernmark A. Autoantibodies in IDDM primarily recognize the 65,000-M(r) rather than the 67,000-M(r) isoform of glutamic acid decarboxylase. Diabetes. 1993 Apr;42(4):631–636. doi: 10.2337/diab.42.4.631. [DOI] [PubMed] [Google Scholar]
- Hamaguchi K., Leiter E. H. Comparison of cytokine effects on mouse pancreatic alpha-cell and beta-cell lines. Viability, secretory function, and MHC antigen expression. Diabetes. 1990 Apr;39(4):415–425. doi: 10.2337/diab.39.4.415. [DOI] [PubMed] [Google Scholar]
- Hassouna N., Michot B., Bachellerie J. P. The complete nucleotide sequence of mouse 28S rRNA gene. Implications for the process of size increase of the large subunit rRNA in higher eukaryotes. Nucleic Acids Res. 1984 Apr 25;12(8):3563–3583. doi: 10.1093/nar/12.8.3563. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jitsukawa T., Nakajima S., Sugawara I., Watanabe H. Increased coating efficiency of antigens and preservation of original antigenic structure after coating in ELISA. J Immunol Methods. 1989 Jan 17;116(2):251–257. doi: 10.1016/0022-1759(89)90211-1. [DOI] [PubMed] [Google Scholar]
- Johnston T. C., Thompson R. B., Baldwin T. O. Nucleotide sequence of the luxB gene of Vibrio harveyi and the complete amino acid sequence of the beta subunit of bacterial luciferase. J Biol Chem. 1986 Apr 15;261(11):4805–4811. [PubMed] [Google Scholar]
- Karjalainen J., Martin J. M., Knip M., Ilonen J., Robinson B. H., Savilahti E., Akerblom H. K., Dosch H. M. A bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus. N Engl J Med. 1992 Jul 30;327(5):302–307. doi: 10.1056/NEJM199207303270502. [DOI] [PubMed] [Google Scholar]
- Karjalainen J., Saukkonen T., Savilahti E., Dosch H. M. Disease-associated anti-bovine serum albumin antibodies in type 1 (insulin-dependent) diabetes mellitus are detected by particle concentration fluoroimmunoassay, and not by enzyme linked immunoassay. Diabetologia. 1992 Oct;35(10):985–990. doi: 10.1007/BF00401430. [DOI] [PubMed] [Google Scholar]
- Karounos D. G., Thomas J. W. Recognition of common islet antigen by autoantibodies from NOD mice and humans with IDDM. Diabetes. 1990 Sep;39(9):1085–1090. doi: 10.2337/diab.39.9.1085. [DOI] [PubMed] [Google Scholar]
- Kaufman D. L., Erlander M. G., Clare-Salzler M., Atkinson M. A., Maclaren N. K., Tobin A. J. Autoimmunity to two forms of glutamate decarboxylase in insulin-dependent diabetes mellitus. J Clin Invest. 1992 Jan;89(1):283–292. doi: 10.1172/JCI115573. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Klein P., Kanehisa M., DeLisi C. The detection and classification of membrane-spanning proteins. Biochim Biophys Acta. 1985 May 28;815(3):468–476. doi: 10.1016/0005-2736(85)90375-x. [DOI] [PubMed] [Google Scholar]
- Kohler P. O., Bridson W. E., Hammond J. M., Weintraub B., Kirschner M. A., Van Thiel D. H. Clonal lines of human choriocarcinoma cells in culture. Acta Endocrinol Suppl (Copenh) 1971;153:137–153. doi: 10.1530/acta.0.068s137. [DOI] [PubMed] [Google Scholar]
- Kozak M. An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 1987 Oct 26;15(20):8125–8148. doi: 10.1093/nar/15.20.8125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kumar K. N., Eggeman K. T., Adams J. L., Michaelis E. K. Hydrodynamic properties of the purified glutamate-binding protein subunit of the N-methyl-D-aspartate receptor. J Biol Chem. 1991 Aug 15;266(23):14947–14952. [PubMed] [Google Scholar]
- Kumar K. N., Tilakaratne N., Johnson P. S., Allen A. E., Michaelis E. K. Cloning of cDNA for the glutamate-binding subunit of an NMDA receptor complex. Nature. 1991 Nov 7;354(6348):70–73. doi: 10.1038/354070a0. [DOI] [PubMed] [Google Scholar]
- Kyte J., Doolittle R. F. A simple method for displaying the hydropathic character of a protein. J Mol Biol. 1982 May 5;157(1):105–132. doi: 10.1016/0022-2836(82)90515-0. [DOI] [PubMed] [Google Scholar]
- Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
- Lander E. S., Green P., Abrahamson J., Barlow A., Daly M. J., Lincoln S. E., Newberg L. A., Newburg L. MAPMAKER: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations. Genomics. 1987 Oct;1(2):174–181. doi: 10.1016/0888-7543(87)90010-3. [DOI] [PubMed] [Google Scholar]
- Leiter E. H., Serreze D. V. Antigen presenting cells and the immunogenetics of autoimmune diabetes in NOD mice. Reg Immunol. 1992 Sep-Oct;4(5):263–273. [PubMed] [Google Scholar]
- Maina C. V., Riggs P. D., Grandea A. G., 3rd, Slatko B. E., Moran L. S., Tagliamonte J. A., McReynolds L. A., Guan C. D. An Escherichia coli vector to express and purify foreign proteins by fusion to and separation from maltose-binding protein. Gene. 1988 Dec 30;74(2):365–373. doi: 10.1016/0378-1119(88)90170-9. [DOI] [PubMed] [Google Scholar]
- Martin J. M., Trink B., Daneman D., Dosch H. M., Robinson B. Milk proteins in the etiology of insulin-dependent diabetes mellitus (IDDM). Ann Med. 1991 Oct;23(4):447–452. doi: 10.3109/07853899109148088. [DOI] [PubMed] [Google Scholar]
- Mason D. Y., Sammons R. Alkaline phosphatase and peroxidase for double immunoenzymatic labelling of cellular constituents. J Clin Pathol. 1978 May;31(5):454–460. doi: 10.1136/jcp.31.5.454. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McCauliffe D. P., Lux F. A., Lieu T. S., Sanz I., Hanke J., Newkirk M. M., Bachinski L. L., Itoh Y., Siciliano M. J., Reichlin M. Molecular cloning, expression, and chromosome 19 localization of a human Ro/SS-A autoantigen. J Clin Invest. 1990 May;85(5):1379–1391. doi: 10.1172/JCI114582. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Palmer J. P., Asplin C. M., Clemons P., Lyen K., Tatpati O., Raghu P. K., Paquette T. L. Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science. 1983 Dec 23;222(4630):1337–1339. doi: 10.1126/science.6362005. [DOI] [PubMed] [Google Scholar]
- Pari G., Jardine K., McBurney M. W. Multiple CArG boxes in the human cardiac actin gene promoter required for expression in embryonic cardiac muscle cells developing in vitro from embryonal carcinoma cells. Mol Cell Biol. 1991 Sep;11(9):4796–4803. doi: 10.1128/mcb.11.9.4796. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Powers A. C., Efrat S., Mojsov S., Spector D., Habener J. F., Hanahan D. Proglucagon processing similar to normal islets in pancreatic alpha-like cell line derived from transgenic mouse tumor. Diabetes. 1990 Apr;39(4):406–414. doi: 10.2337/diab.39.4.406. [DOI] [PubMed] [Google Scholar]
- Prochazka M., Leiter E. H., Serreze D. V., Coleman D. L. Three recessive loci required for insulin-dependent diabetes in nonobese diabetic mice. Science. 1987 Jul 17;237(4812):286–289. doi: 10.1126/science.2885918. [DOI] [PubMed] [Google Scholar]
- Prochazka M., Serreze D. V., Worthen S. M., Leiter E. H. Genetic control of diabetogenesis in NOD/Lt mice. Development and analysis of congenic stocks. Diabetes. 1989 Nov;38(11):1446–1455. doi: 10.2337/diab.38.11.1446. [DOI] [PubMed] [Google Scholar]
- Purrello F., Buscema M., Vetri M., Vinci C., Gatta C., Forte F., Rabuazzo A. M., Vigneri R. Glucose regulates both glucose transport and the glucose transporter gene expression in a hamster-derived pancreatic beta-cell line (HIT). Diabetologia. 1991 May;34(5):366–369. doi: 10.1007/BF00405011. [DOI] [PubMed] [Google Scholar]
- Rabin D. U., Pleasic S. M., Palmer-Crocker R., Shapiro J. A. Cloning and expression of IDDM-specific human autoantigens. Diabetes. 1992 Feb;41(2):183–186. doi: 10.2337/diab.41.2.183. [DOI] [PubMed] [Google Scholar]
- Raynal F., Michot B., Bachellerie J. P. Complete nucleotide sequence of mouse 18 S rRNA gene: comparison with other available homologs. FEBS Lett. 1984 Feb 27;167(2):263–268. doi: 10.1016/0014-5793(84)80139-8. [DOI] [PubMed] [Google Scholar]
- Roep B. O., Kallan A. A., Hazenbos W. L., Bruining G. J., Bailyes E. M., Arden S. D., Hutton J. C., de Vries R. R. T-cell reactivity to 38 kD insulin-secretory-granule protein in patients with recent-onset type 1 diabetes. Lancet. 1991 Jun 15;337(8755):1439–1441. doi: 10.1016/0140-6736(91)93127-u. [DOI] [PubMed] [Google Scholar]
- Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Spritz R. A., Strunk K., Surowy C. S., Hoch S. O., Barton D. E., Francke U. The human U1-70K snRNP protein: cDNA cloning, chromosomal localization, expression, alternative splicing and RNA-binding. Nucleic Acids Res. 1987 Dec 23;15(24):10373–10391. doi: 10.1093/nar/15.24.10373. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sun X. J., Rothenberg P., Kahn C. R., Backer J. M., Araki E., Wilden P. A., Cahill D. A., Goldstein B. J., White M. F. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature. 1991 Jul 4;352(6330):73–77. doi: 10.1038/352073a0. [DOI] [PubMed] [Google Scholar]
- Tabor S., Richardson C. C. DNA sequence analysis with a modified bacteriophage T7 DNA polymerase. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4767–4771. doi: 10.1073/pnas.84.14.4767. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tan E. M. Autoantibodies in pathology and cell biology. Cell. 1991 Nov 29;67(5):841–842. doi: 10.1016/0092-8674(91)90356-4. [DOI] [PubMed] [Google Scholar]
- Thivolet C. H., Tappaz M., Durand A., Petersen J., Stefanutti A., Chatelain P., Vialettes B., Scherbaum W., Orgiazzi J. Glutamic acid decarboxylase (GAD) autoantibodies are additional predictive markers of type 1 (insulin-dependent) diabetes mellitus in high risk individuals. Diabetologia. 1992 Jun;35(6):570–576. doi: 10.1007/BF00400486. [DOI] [PubMed] [Google Scholar]
- Thomas P. S. Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5201–5205. doi: 10.1073/pnas.77.9.5201. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wallace R. B., Johnson M. J., Hirose T., Miyake T., Kawashima E. H., Itakura K. The use of synthetic oligonucleotides as hybridization probes. II. Hybridization of oligonucleotides of mixed sequence to rabbit beta-globin DNA. Nucleic Acids Res. 1981 Feb 25;9(4):879–894. doi: 10.1093/nar/9.4.879. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Walter G. Production and use of antibodies against synthetic peptides. J Immunol Methods. 1986 Apr 17;88(2):149–161. doi: 10.1016/0022-1759(86)90001-3. [DOI] [PubMed] [Google Scholar]
- Young R. A., Davis R. W. Yeast RNA polymerase II genes: isolation with antibody probes. Science. 1983 Nov 18;222(4625):778–782. doi: 10.1126/science.6356359. [DOI] [PubMed] [Google Scholar]
- Zhang Z. J., Davidson L., Eisenbarth G., Weiner H. L. Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10252–10256. doi: 10.1073/pnas.88.22.10252. [DOI] [PMC free article] [PubMed] [Google Scholar]