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Alternative transcripts and evidence of imprinting of GNAL on 18p11.2

Abstract

Genetic studies implicating the region of human chromosome 18p11.2 in susceptibility to bipolar disorder and schizophrenia have observed parent-of-origin effects that may be explained by genomic imprinting. We have identified a transcriptional variant of the GNAL gene in this region, employing an alternative first exon that is 5′ to the originally identified start site. This alternative GNAL transcript encodes a longer functional variant of the stimulatory G-protein alpha subunit, Golf. The isoforms of Golf display different expression patterns in the CNS and functionally couple to the dopamine D1 receptor when heterologously expressed in Sf9 cells. In addition, there are CpG islands in the vicinity of both first exons that are differentially methylated, a hallmark of genomic imprinting. These results suggest that GNAL, and possibly other genes in the region, is subject to epigenetic regulation and strengthen the case for a susceptibility gene in this region.

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References

  1. Berrettini WH, Ferraro TN, Goldin LR, Weeks DE, Detera-Wadleigh S, Nurnberger Jr JI et al. Chromosome 18 DNA markers and manic-depressive illness: evidence for a susceptibility gene. Proc Natl Acad Sci USA 1994; 91: 5918–5921.

    Article  CAS  Google Scholar 

  2. Stine OC, Xu J, Koskela R, McMahon FJ, Gschwend M, Friddle C et al. Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect. Am J Hum Genet 1995; 57: 1384–1394.

    PubMed  PubMed Central  CAS  Google Scholar 

  3. Nothen MM, Cichon S, Rohleder H, Hemmer S, Franzek E, Fritze J et al. Evaluation of linkage of bipolar affective disorder to chromosome 18 in a sample of 57 German families. Mol Psychiatry 1999; 4: 76–84.

    Article  CAS  Google Scholar 

  4. Schwab SG, Hallmayer J, Lerer B, Albus M, Borrmann M, Honig S et al. Support for a chromosome 18p locus conferring susceptibility to functional psychoses in families with schizophrenia, by association and linkage analysis. Am J Hum Genet 1998; 63: 1139–1152.

    Article  CAS  Google Scholar 

  5. Manji HK, Lenox RH . The nature of bipolar disorder. J Clin Psychiatry 2000; 61(Suppl 13): 42–57.

    PubMed  Google Scholar 

  6. Miki M, Hamamura T, Ujike H, Lee Y, Habara T, Kodama M et al. Effects of subchronic lithium chloride treatment on G-protein subunits (Golf, Ggamma7) and adenylyl cyclase expressed specifically in the rat striatum. Eur J Pharmacol 2001; 428: 303–309.

    Article  CAS  Google Scholar 

  7. Li LC, Dahiya R . MethPrimer: designing primers for methylation PCRs. Bioinformatics 2002; 18: 1427–1431.

    Article  CAS  Google Scholar 

  8. Vuoristo JT, Berrettini WH, Overhauser J, Prockop DJ, Ferraro TN, Ala-Kokko L . Sequence and genomic organization of the human G-protein Golfalpha gene (GNAL) on chromosome 18p11, a susceptibility region for bipolar disorder and schizophrenia. Mol Psychiatry 2000; 5: 495–501.

    Article  CAS  Google Scholar 

  9. Kehlenbach RH, Matthey J, Huttner WB . XL alphas is a new type of G protein. Nature 1994; 372: 804–809.

    Article  CAS  Google Scholar 

  10. Herve D, Rogard M, Levi-Strauss M . Molecular analysis of the multiple Golf alpha subunit mRNAs in the rat brain. Brain Res Mol Brain Res 1995; 32: 125–134.

    Article  CAS  Google Scholar 

  11. Belluscio L, Gold GH, Nemes A, Axel R . Mice deficient in G(olf) are anosmic. Neuron 1998; 20: 69–81.

    Article  CAS  Google Scholar 

  12. Zhuang X, Belluscio L, Hen R . G(olf) alpha mediates dopamine D1 receptor signaling. J Neurosci 2000; 20: RC91.

    Article  CAS  Google Scholar 

  13. Corvol JC, Studler JM, Schonn JS, Girault JA, Herve D . Galpha(olf) is necessary for coupling D1 and A2a receptors to adenylyl cyclase in the striatum. J Neurochem 2001; 76: 1585–1588.

    Article  CAS  Google Scholar 

  14. Hayward BE, Moran V, Strain L, Bonthron DT . Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins. Proc Natl Acad Sci USA 1998; 95: 15475–15480.

    Article  CAS  Google Scholar 

  15. Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB . Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996; 93: 9821–9826.

    Article  CAS  Google Scholar 

  16. Costello JF, Fruhwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X et al. Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat Genet 2000; 24: 132–138.

    Article  CAS  Google Scholar 

  17. Ischia R, Lovisetti-Scamihorn P, Hogue-Angeletti R, Wolkersdorfer M, Winkler H, Fischer-Colbrie R . Molecular cloning and characterization of NESP55, a novel chromogranin-like precursor of a peptide with 5-HT1B receptor antagonist activity. J Biol Chem 1997; 272: 11657–11662.

    Article  CAS  Google Scholar 

  18. Weiss U, Ischia R, Eder S, Lovisetti-Scamihorn P, Bauer R, Fischer-Colbrie R . Neuroendocrine secretory protein 55 (NESP55): alternative splicing onto transcripts of the GNAS gene and posttranslational processing of a maternally expressed protein. Neuroendocrinology 2000; 71: 177–186.

    Article  CAS  Google Scholar 

  19. Gille A, Seifert R . Co-expression of the beta2-adrenoceptor and dopamine D1-receptor with Gsalpha proteins in Sf9 insect cells: limitations in comparison with fusion proteins. Biochim Biophys Acta 2003; 1613: 101–114.

    Article  CAS  Google Scholar 

  20. George SR, Lee SP, Varghese G, Zeman PR, Seeman P, Ng GY et al. A transmembrane domain-derived peptide inhibits D1 dopamine receptor function without affecting receptor oligomerization. J Biol Chem 1998; 273: 30244–30248.

    Article  CAS  Google Scholar 

  21. Leopoldt D, Harteneck C, Nurnberg B . G proteins endogenously expressed in Sf 9 cells: interactions with mammalian histamine receptors. Naunyn-Schmiedeberg's Arch Pharmacol 1997; 356: 216–224.

    Article  CAS  Google Scholar 

  22. Herve D, Le Moine C, Corvol JC, Belluscio L, Ledent C, Fienberg AA et al. Galpha(olf) levels are regulated by receptor usage and control dopamine and adenosine action in the striatum. J Neurosci 2001; 21: 4390–4399.

    Article  CAS  Google Scholar 

  23. Zahniser NR, Simosky JK, Mayfield RD, Negri CA, Hanania T, Larson GA et al. Functional uncoupling of adenosine A(2A) receptors and reduced response to caffeine in mice lacking dopamine D2 receptors. J Neurosci 2000; 20: 5949–5957.

    Article  CAS  Google Scholar 

  24. Zhang D, Zhang L, Lou DW, Nakabeppu Y, Zhang J, Xu M . The dopamine D1 receptor is a critical mediator for cocaine-induced gene expression. J Neurochem 2002; 82: 1453–1464.

    Article  CAS  Google Scholar 

  25. Weinstein LS, Yu S, Warner DR, Liu J . Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting. Endocr Rev 2001; 22: 675–705.

    PubMed  CAS  Google Scholar 

  26. Reik W, Walter J . Genomic imprinting: parental influence on the genome. Nat Rev Genet 2001; 2: 21–32.

    Article  CAS  Google Scholar 

  27. Vuoristo JT, Ala-Kokko L . cDNA cloning, genomic organization and expression of the novel human metallophosphoesterase gene MPPE1 on chromosome 18p11.2. Cytogenet Cell Genet 2001; 95: 60–63.

    Article  CAS  Google Scholar 

  28. Yoshikawa T, Kikuchi M, Saito K, Watanabe A, Yamada K, Shibuya H et al. Evidence for association of the myo-inositol monophosphatase 2 (IMPA2) gene with schizophrenia in Japanese samples. Mol Psychiatry 2001; 6: 202–210.

    Article  CAS  Google Scholar 

  29. Sjoholt G, Ebstein RP, Lie RT, Berle J, Mallet J, Deleuze JF et al. Examination of IMPA1 and IMPA2 genes in maniac-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder. Mol Psychiatry 2003; 23: 23.

    Google Scholar 

  30. Berrettini WH, Vuoristo J, Ferraro TN, Buono RJ, Wildenauer D, Ala-Kokko L . Human G(olf) gene polymorphisms and vulnerability to bipolar disorder. Psychiatr Genet 1998; 8: 235–238.

    Article  CAS  Google Scholar 

  31. Tsiouris SJ, Breschel TS, Xu J, McInnis MG, McMahon FJ . Linkage disequilibrium analysis of G-olf alpha (GNAL) in bipolar affective disorder. Am J Med Genet 1996; 67: 491–494.

    Article  CAS  Google Scholar 

  32. Zill P, Engel R, Baghai TC, Zwanzger P, Schule C, Minov C et al. Analysis of polymorphisms in the olfactory G-protein Golf in major depression. Psychiatr Genet 2002; 12: 17–22.

    Article  Google Scholar 

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Acknowledgements

We gratefully acknowledge Greg Golden at the Veterans Affairs Medical Center in Coatesville, PA, for providing the human brain tissue.

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Correspondence to S T Furlong.

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Corradi, J., Ravyn, V., Robbins, A. et al. Alternative transcripts and evidence of imprinting of GNAL on 18p11.2. Mol Psychiatry 10, 1017–1025 (2005). https://doi.org/10.1038/sj.mp.4001713

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