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Gene Review

GAD2  -  glutamate decarboxylase 2 (pancreatic...

Homo sapiens

Synonyms: 65 kDa glutamic acid decarboxylase, GAD-65, GAD65, Glutamate decarboxylase 2, Glutamate decarboxylase 65 kDa isoform
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Disease relevance of GAD2

  • GAD2 on chromosome 10p12 is a candidate gene for human obesity [1].
  • In the murine insulinoma cell line betaTC3, the G at-risk allele of SNP -243 A>G increased six times GAD2 promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts [1].
  • We describe the use homology modelling, protein-protein docking simulations and biopanning of random peptide phage displayed libraries with b96.11 to predict contact amino acids on the interface of GAD65/Fab b96.11 complex [2].
  • The data illustrate that antibodies against GAD-65 are present in a majority of patients with type 1 diabetes mellitus and that autoantibodies against other islet cell antigens also exist [3].
  • It is interesting that human pituitary GH adenomas share expression of VGAT and GABA receptors with normal pituitary glands but lack GAD 65 [4].

Psychiatry related information on GAD2

  • These results confirm the association between GAD2-243 promoter SNP and the risk for obesity and suggest that GAD2 may be a polygenic component of the complex mechanisms linking birth weight to further risk for metabolic diseases, possibly involving the pleiotropic effect of insulin on fetal growth and later on feeding behavior [5].
  • CONCLUSION: Bipolar disorder is associated with organ-specific autoimmunity to the antigens TPO, H/K ATPase, and GAD65 [6].
  • Therefore, individual differences in Ag processing may result in the presentation of distinct set of peptides derived from an autoantigen such as GAD65 [7].
  • CONCLUSION: This study demonstrates for the first time significant deficits in GABAergic markers Reelin and GAD 65 and 67 proteins in bipolar subjects and global deficits in the latter proteins in schizophrenia and mood disorders, accounting for the reported alterations in CSF/plasma levels of glutamate and GABA in these disorders [8].

High impact information on GAD2


Chemical compound and disease context of GAD2


Biological context of GAD2

  • We have genotyped these polymorphisms in a maximum of 472 U.K. type 1 diabetic affected sib pair families exhibiting linkage to type 1 diabetes on chromosome 10p and have tested both single variants and haplotypes in the GAD2 region for association with disease [16].
  • We have therefore systematically searched all exons, the 3' untranslated region (UTR), the 5' UTR, and the 5' upstream region of GAD2, for polymorphisms in 32 white European individuals [16].
  • In each family, the affected siblings exhibited different genotypes for the GAD2 gene; in two families the GAD1 genotype was disparate [17].
  • GAD2, previously mapped to human chromosome 10p11.2-p12, was mapped to mouse chromosome 2A2-B, which identifies a new region of conservation between human and mouse chromosomes [18].
  • Three valid SNPs at the GAD2 gene demonstrated no associations with alcoholism [19].

Anatomical context of GAD2

  • As GAD2 is highly expressed in pancreatic beta cells, we analyzed GAD65 antibody level as a marker of beta-cell activity and of insulin secretion [1].
  • Using sequence information from GAD-1 to screen a human pancreatic islet cDNA library, we describe the isolation of an additional GAD cDNA (GAD-2), which was mapped to the short arm of human chromosome 10 [20].
  • Subsequently, [35S]methionine-labeled GAD-65 was purified from COS cell lysates and employed in a binding assay with 50 sera of patients with recent onset of type 1 diabetes mellitus [3].
  • A Golgi localization signal in aa 1-23 followed by a membrane anchoring signal upstream of the palmitoylation motif are required for this process and mediate targeting of GAD65 to the cytosolic leaflet of Golgi membranes, an obligatory first step in axonal sorting [21].
  • Reduction of cellular cholesterol levels resulted in the inhibition of presynaptic clustering of palmitoylated GAD65, suggesting that the selective targeting of the protein to presynaptic termini is dependent on sorting to cholesterol-rich membrane microdomains [21].

Associations of GAD2 with chemical compounds

  • Structural and functional analysis of cysteine residues in human glutamate decarboxylase 65 (GAD65) and GAD67 [22].
  • The predicted GAD2 protein sequence is similar to 2-oxoglutarate-dependent dioxygenases while the predicted GAD3 protein sequence is similar to proteins belonging to the nonmetallo-short-chain alcohol-dehydrogenase family, especially the T ASSELSEED2 (TS2) gene of maize and bacterial hydroxysteroid dehydrogenases [23].
  • Treatment with abscisic acid (ABA) antagonizes the GA-induced suppression of the GAD1 and GAD2 RNAs [23].
  • Here we show that targeting of the gamma-aminobutyric acid-synthesizing enzyme glutamate decarboxylase 65 (GAD65) to presynaptic clusters is mediated by its palmitoylated 60-aa NH(2)-terminal domain and that this region can target other soluble proteins and their associated partners to presynaptic termini [21].
  • RESULTS: The introduction of a point mutation at position 517, substituting glutamic acid with proline, markedly reduced the binding of disease-associated GAD65 antibodies [24].

Physical interactions of GAD2


Co-localisations of GAD2


Regulatory relationships of GAD2

  • In the human DLPFC, GAD65 mRNA was found to be expressed significantly less than the message for GAD67, approximately 16% of that observed for GAD67 [28].
  • Virtually all TH-labeled neurons expressed GAD65 mRNA, about 30% of them exhibited calretinin, but none stained for the other striatal neuron markers [29].
  • However, the relative (compared with 0 months) glucagon-stimulated C-peptide response was more than 30% lower in GAD65 Ab+ patients receiving placebo at 9 and 12 months compared with the GAD65 Ab- placebo patients (P < 0.035) [30].

Other interactions of GAD2

  • Moreover, interference with endogenous expression of HIP14 reduces clustering of PSD-95 and GAD65 in neurons [31].
  • The GAD1 (2q31) and GAD2 genes (10p23) were tested and excluded [32].
  • We examined the ability of ECs expressing HLA class II molecules to process and present the islet autoantigen GAD65 and examined the effects of presentation on transmigration of GAD65-specific T-cells [33].
  • Using comprehensive peptide libraries that cover the entire sequence of two major candidate autoantigens, GAD65 and proinsulin, we measured the in vivo frequencies of peptide-specific, IFN-gamma-producing memory T cells in 27 diabetic patients, 14 high risk individuals, and 15 partially HLA-matched healthy controls [34].
  • Expression of GAD65 and GAD67 mRNA in the DLPFC and in the occipital cortex was significantly elevated in patients with schizophrenia, whereas the expression of the corresponding proteins and GAT-1 mRNA was unchanged [28].

Analytical, diagnostic and therapeutic context of GAD2


  1. GAD2 on chromosome 10p12 is a candidate gene for human obesity. Boutin, P., Dina, C., Vasseur, F., Dubois, S., Corset, L., Séron, K., Bekris, L., Cabellon, J., Neve, B., Vasseur-Delannoy, V., Chikri, M., Charles, M.A., Clement, K., Lernmark, A., Froguel, P. PLoS Biol. (2003) [Pubmed]
  2. Molecular characterization of a disease associated conformational epitope on GAD65 recognised by a human monoclonal antibody b96.11. Fenalti, G., Hampe, C.S., O'connor, K., Banga, J.P., Mackay, I.R., Rowley, M.J., El-Kabbani, O. Mol. Immunol. (2007) [Pubmed]
  3. Demonstration of GAD-65 as the main immunogenic isoform of glutamate decarboxylase in type 1 diabetes and determination of autoantibodies using a radioligand produced by eukaryotic expression. Velloso, L.A., Kämpe, O., Hallberg, A., Christmanson, L., Betsholtz, C., Karlsson, F.A. J. Clin. Invest. (1993) [Pubmed]
  4. Receptors and sites of synthesis and storage of gamma-aminobutyric acid in human pituitary glands and in growth hormone adenomas. End, K., Gamel-Didelon, K., Jung, H., Tolnay, M., Lüdecke, D., Gratzl, M., Mayerhofer, A. Am. J. Clin. Pathol. (2005) [Pubmed]
  5. Is glutamate decarboxylase 2 (GAD2) a genetic link between low birth weight and subsequent development of obesity in children? Meyre, D., Boutin, P., Tounian, A., Deweirder, M., Aout, M., Jouret, B., Heude, B., Weill, J., Tauber, M., Tounian, P., Froguel, P. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  6. A high prevalence of organ-specific autoimmunity in patients with bipolar disorder. Padmos, R.C., Bekris, L., Knijff, E.M., Tiemeier, H., Kupka, R.W., Cohen, D., Nolen, W.A., Lernmark, A., Drexhage, H.A. Biol. Psychiatry (2004) [Pubmed]
  7. Differential presentation of glutamic acid decarboxylase 65 (GAD65) T cell epitopes among HLA-DRB1*0401-positive individuals. Reijonen, H., Elliott, J.F., van Endert, P., Nepom, G. J. Immunol. (1999) [Pubmed]
  8. GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum. Fatemi, S.H., Hossein Fatemi, S., Stary, J.M., Earle, J.A., Araghi-Niknam, M., Eagan, E. Schizophr. Res. (2005) [Pubmed]
  9. High-dose intravenous immune globulin for stiff-person syndrome. Dalakas, M.C., Fujii, M., Li, M., Lutfi, B., Kyhos, J., McElroy, B. N. Engl. J. Med. (2001) [Pubmed]
  10. Higher autoantibody levels and recognition of a linear NH2-terminal epitope in the autoantigen GAD65, distinguish stiff-man syndrome from insulin-dependent diabetes mellitus. Kim, J., Namchuk, M., Bugawan, T., Fu, Q., Jaffe, M., Shi, Y., Aanstoot, H.J., Turck, C.W., Erlich, H., Lennon, V., Baekkeskov, S. J. Exp. Med. (1994) [Pubmed]
  11. Improved in planta expression of the human islet autoantigen glutamic acid decarboxylase (GAD65). Avesani, L., Falorni, A., Tornielli, G.B., Marusic, C., Porceddu, A., Polverari, A., Faleri, C., Calcinaro, F., Pezzotti, M. Transgenic Res. (2003) [Pubmed]
  12. Time-resolved fluorometric assay for detection of autoantibodies to glutamic acid decarboxylase (GAD65). Ankelo, M., Westerlund-Karlsson, A., Ilonen, J., Knip, M., Savola, K., Kankaanpää, P., Meriö, L., Siitari, H., Hinkkanen, A. Clin. Chem. (2003) [Pubmed]
  13. Intradermal skin test with diabetes specific antigens in patients with type 1 diabetes. Crinò, A., Cavallo, M.G., Corbi, S., Mesturino, C.A., Ferrazzoli, F., Coppolino, G., Bizzarri, C., Cervoni, M., Monetini, L., Pozzilli, P. Clin. Exp. Immunol. (2001) [Pubmed]
  14. Tyrosine phosphatase-like protein (IA-2) and glutamic acid decarboxylase (GAD65) autoantibodies: a study of Chinese patients with diabetes mellitus. Ng, W.Y., Lee, Y.S., Todd, A.L., Lui, K.F., Loke, K.Y., Thai, A.C. Autoimmunity (2002) [Pubmed]
  15. Lack of association of glutamate decarboxylase 2 gene polymorphisms with severe obesity in utah. Hunt, S.C., Xin, Y., Wu, L.L., Hopkins, P.N., Adams, T.D. Obesity (Silver Spring, Md.) (2006) [Pubmed]
  16. A comprehensive, statistically powered analysis of GAD2 in type 1 diabetes. Johnson, G.C., Payne, F., Nutland, S., Stevens, H., Tuomilehto-Wolf, E., Tuomilehto, J., Todd, J.A. Diabetes (2002) [Pubmed]
  17. Glutamate decarboxylase is not genetically linked to pyridoxine-dependent seizures. Battaglioli, G., Rosen, D.R., Gospe, S.M., Martin, D.L. Neurology (2000) [Pubmed]
  18. Mapping of glutamic acid decarboxylase (GAD) genes. Edelhoff, S., Grubin, C.E., Karlsen, A.E., Alder, D.A., Foster, D., Disteche, C.M., Lernmark, A. Genomics (1993) [Pubmed]
  19. Glutamate decarboxylase genes and alcoholism in han taiwanese men. Loh, e.l.-.W., Lane, H.Y., Chen, C.H., Chang, P.S., Ku, L.W., Wang, K.H., Cheng, A.T. Alcohol. Clin. Exp. Res. (2006) [Pubmed]
  20. Cloning and primary structure of a human islet isoform of glutamic acid decarboxylase from chromosome 10. Karlsen, A.E., Hagopian, W.A., Grubin, C.E., Dube, S., Disteche, C.M., Adler, D.A., Bärmeier, H., Mathewes, S., Grant, F.J., Foster, D. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  21. A combination of three distinct trafficking signals mediates axonal targeting and presynaptic clustering of GAD65. Kanaani, J., el-Husseini, A.e.l.-.D., Aguilera-Moreno, A., Diacovo, J.M., Bredt, D.S., Baekkeskov, S. J. Cell Biol. (2002) [Pubmed]
  22. Structural and functional analysis of cysteine residues in human glutamate decarboxylase 65 (GAD65) and GAD67. Wei, J., Wu, J.Y. J. Neurochem. (2005) [Pubmed]
  23. Gibberellins regulate the abundance of RNAs with sequence similarity to proteinase inhibitors, dioxygenases and dehydrogenases. Jacobsen, S.E., Olszewski, N.E. Planta (1996) [Pubmed]
  24. Conformation-dependent GAD65 autoantibodies in diabetes. Luo, D., Gilliam, L.K., Greenbaum, C., Bekris, L., Hampe, C.S., Daniels, T., Richter, W., Marcovina, S.M., Rolandsson, O., Landin-Olsson, M., Kockum, I., Lernmark, A. Diabetologia (2004) [Pubmed]
  25. Characterisation of an autoreactive conformational epitope on GAD65 recognised by the human monoclonal antibody b78 using a combination of phage display, in vitro mutagenesis and molecular modelling. O'Connor, K.H., Banga, J.P., Darmanin, C., El-Kabbani, O., Mackay, I.R., Rowley, M.J. J. Autoimmun. (2006) [Pubmed]
  26. Comparison of the prevalence of glutamic acid decarboxylase (GAD65) and gliadin antibodies (AGA) in a randomly selected adult estonian population. Uibo, R., Sullivan, E.P., Uibo, O., Lernmark, A., Salur, L., Kivik, T., Mandel, M. Horm. Metab. Res. (2001) [Pubmed]
  27. Targeting of the 67-kDa isoform of glutamic acid decarboxylase to intracellular organelles is mediated by its interaction with the NH2-terminal region of the 65-kDa isoform of glutamic acid decarboxylase. Dirkx, R., Thomas, A., Li, L., Lernmark, A., Sherwin, R.S., De Camilli, P., Solimena, M. J. Biol. Chem. (1995) [Pubmed]
  28. GAD67 and GAD65 mRNA and protein expression in cerebrocortical regions of elderly patients with schizophrenia. Dracheva, S., Elhakem, S.L., McGurk, S.R., Davis, K.L., Haroutunian, V. J. Neurosci. Res. (2004) [Pubmed]
  29. Neurochemical characterization of dopaminergic neurons in human striatum. Cossette, M., Lévesque, D., Parent, A. Parkinsonism Relat. Disord. (2005) [Pubmed]
  30. Glutamic acid decarboxylase (GAD65) autoantibodies in prediction of beta-cell function and remission in recent-onset IDDM after cyclosporin treatment. The Canadian-European Randomized Control Trial Group. Petersen, J.S., Dyrberg, T., Karlsen, A.E., Mølvig, J., Michelsen, B., Nerup, J., Mandrup-Poulsen, T. Diabetes (1994) [Pubmed]
  31. Huntingtin-interacting protein HIP14 is a palmitoyl transferase involved in palmitoylation and trafficking of multiple neuronal proteins. Huang, K., Yanai, A., Kang, R., Arstikaitis, P., Singaraja, R.R., Metzler, M., Mullard, A., Haigh, B., Gauthier-Campbell, C., Gutekunst, C.A., Hayden, M.R., El-Husseini, A. Neuron (2004) [Pubmed]
  32. A gene for pyridoxine-dependent epilepsy maps to chromosome 5q31. Cormier-Daire, V., Dagoneau, N., Nabbout, R., Burglen, L., Penet, C., Soufflet, C., Desguerre, I., Munnich, A., Dulac, O. Am. J. Hum. Genet. (2000) [Pubmed]
  33. Processing and presentation of the islet autoantigen GAD by vascular endothelial cells promotes transmigration of autoreactive T-cells. Greening, J.E., Tree, T.I., Kotowicz, K.T., van Halteren, A.G., Roep, B.O., Klein, N.J., Peakman, M. Diabetes (2003) [Pubmed]
  34. T cells recognize multiple GAD65 and proinsulin epitopes in human type 1 diabetes, suggesting determinant spreading. Ott, P.A., Dittrich, M.T., Herzog, B.A., Guerkov, R., Gottlieb, P.A., Putnam, A.L., Durinovic-Bello, I., Boehm, B.O., Tary-Lehmann, M., Lehmann, P.V. J. Clin. Immunol. (2004) [Pubmed]
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