Vol 1 n° 3 - Nosology and Nosography
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L e t t e r s   t o   t h e   E d i t o r Re: Bipolar Disorders Issue Preliminary  evidence  for  an  association  of  a  G-pro- tein- 3–gene variant with bipolar disorder—The signal transduction pathway is gaining increasing importance both with respect to the understanding of the neurobi- ological basis of bipolar disorders and as a possible tar- get for antidepressant action.1 G-proteins in particular, which convey the signals from receptor to effector pro- teins,  are  key  elements  in  the  regulation  of  cellular responses, such as the increase in intracellular calcium ion concentration [Ca2+]i, an early event of the signal transduction cascade. One of the most consistent find- ings  in  bipolar  patients  has  been  the  observation  of increased [Ca2+]i in the peripheral cells of acute manic patients, which is downregulated to normal after suc- cessful treatment.2 The recently identified variant of a G-protein- 3  subunit  (G 3-s)  has  been  shown  to  be associated  not  only  with  hypertension,  but  also  with increased signal transduction and ion transport activi- ty.3 In the preliminary study we briefly report on here, we investigated whether the functionally active variant G 3-s was more abundant in patients with bipolar dis- order than in controls. We further examined whether the G 3-s allele was associated with an increase in cal- cium ion stimulation in lymphoblasts. Genomic DNA of 111 healthy controls (56 females, 55 males) and 19 patients with bipolar disorder (euthymic at the time of investigation; 9 females, 10 males) was genotyped for the G 3 variant (= T allele). In our con- trols, the T allele frequency (0.28) closely matches that found  in  the  literature  (0.25).4  However,  in  bipolar patients, the T allele (associated with enhanced G-pro- tein activity) was more frequent (Table). When the TT and TC genotypes were analyzed togeth- er (which seems justified, since the phenotype is appar- ently  not  different),  the  difference  between  bipolar patients and controls was significantly different (Fisher exact test, P=0.049). Assessment  of  the  [Ca2+]i  response,  stimulated  via G 3-s in lymphoblasts of 14 controls and 12 patients, showed  that  the  presence  of  the  T  allele  (heterozy- gous  or  homozygous)  leads  to  an  overall  increase  in calcium   response   after   platelet-activating   factor (PAF)  stimulation  (C,  485±109  nM; T,  761±321  nM; P=0.019),    whereas    basal    levels    are    unaffected (C, 76±33 nM; T, 87±29 nM; NS). No significant differ- ence  was  found  between  euthymic  bipolar  patients and controls, although stimulated [Ca2+]i  values were higher in bipolar patients (648±348 nM) than in con- trols (537±189 nM). Although our results are preliminary and need to be confirmed in a large sample, they suggest that genetic variants  in  genes  of  the  transduction  pathway  could contribute to the increased calcium concentration and increased  signal  transduction  reported  during  acute manic  episodes,  thus  supporting  the  calcium-related theory  of  Dubovsky  and  coworkers.5  Several  adapta- tive mechanisms may account for the more or less bal- anced calcium homeostasis observed during and after successful treatment. This, however remains to be elu- cidated in detail. Probands T/T T/C C/C Frequency T Frequency C Fisher exact test Controls (n=111) 8 46 57 0.28 0.72 Bipolar patients (n=19) 2 12 5 0.42* 0.58 P=0.049 Table. Genotypes and allele frequencies of controls and bipolar patients.
Prof Dr Brigitte Bondy, MD; Karin Neumeir, CTA
Psychiatric Clinic, University of Munich
Nußbaumstraße 7
D-80336 Munich
Germany
(e-mail: bb@psy.med.uni-muenchen.de)
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1. Rasenick MM, Chaney KA, Chen J. G-protein–mediated signal transduction as a target of antidepressant and antibipolar drug action: evidence from model systems. J Clin Psychiatry. 1996;57(suppl 13):49-55.
2. Yatham LN, Srisurapanont M, Zis AP, Kusumakar V. Comparative studies of the biological distinction between unipolar and bipolar depression. Life Sci. 1997;61:1445-1455.
3. Siffert W, Rosskopf D, Siffert G, et al. Association of human G-protein-beta 3 subunit variant with hypertension. Nat Genet. 1998;18:45-48.
4. Siffert W. G-proteins and hypertension: an alternative candidate gene approach. Kidney Int. 1998;53:1466-1470.
5. Dubovsky SL, Murphy J, Thomas M, Rademacher J. Abnormal intracellular calcium ion concentration in platelets and lymphocytes of bipolar patients. Am J Psychiatry.