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Logo of behbrainBioMed CentralBiomed Central Web Sitesearchsubmit a manuscriptregisterthis articleBehavioral and Brain Functions : BBFJournal Front Page
Behav Brain Funct. 2008; 4: 2.
Published online Jan 17, 2008. doi:  10.1186/1744-9081-4-2
PMCID: PMC2267477
Association between the PPP3CC gene, coding for the calcineurin gamma catalytic subunit, and bipolar disorder
Flavie Mathieu,#1,2 Stéphanie Miot,#1 Bruno Etain,1,2 Marie-Anne El Khoury,1 Fabien Chevalier,1 Frank Bellivier,1,2 Marion Leboyer,1,2 Bruno Giros,1 and Eleni T Tzavaracorresponding author1,2
1INSERM U-513, Faculté de Médecine, 8 rue de Général Sarrail, 94000, Créteil, France
2AP-HP, Albert Chenevier and Henri Mondor Hospitals, Department of Psychiatry, 94000, Créteil, France
corresponding authorCorresponding author.
#Contributed equally.
Flavie Mathieu: flavie.mathieu/at/; Stéphanie Miot: stephaniemiot/at/; Bruno Etain: bruno.etain/at/; Marie-Anne El Khoury: marie-anne.elkhoury/at/; Fabien Chevalier: chevalier/at/; Frank Bellivier: frank.bellivier/at/; Marion Leboyer: marion.leboyer/at/; Bruno Giros: bruno.giros/at/; Eleni T Tzavara: eleni.tzavara/at/
Received October 2, 2007; Accepted January 17, 2008.
Calcineurin is a neuron-enriched phosphatase that regulates synaptic plasticity and neuronal adaptation. Activation of calcineurin, overall, antagonizes the effects of the cyclic AMP activated protein/kinase A. Thus, kinase/phosphatase dynamic balance seems to be critical for transition to long-term cellular responses in neurons, and disruption of this equilibrium should induce behavioral impairments in animal models. Genetic animal models, as well as post-mortem studies in humans have implicated calcineurin dependent calcium and cyclic AMP regulated phosphorylation/dephosphorylation in both affective responses and psychosis. Recently, genetic association between schizophrenia and genetic variation of the human calcineurin A gamma subunit gene (PPP3CC) has been reported.
Based on the assumption of the common underlying genetic factor in schizophrenia and bipolar affective disorder (BPAD), we performed association analysis of CC33 and CCS3 polymorphisms of the PPP3CC gene reported to be associated with schizophrenia in a French sample of 115 BPAD patients and 97 healthy controls.
Carrying 'CT' or 'TT' genotypes of the PPP3CC-CC33 polymorphism increased risk to develop BPAD comparing to carry 'CC' genotype (OR = 1.8 [1.01–3.0]; p = 0.05). For the PPP3CC-CCS3 polymorphism, 'AG' or 'GG' carriers have an increased risk to develop BPAD than 'AA' carriers (OR = 2.8 [1.5–5.2]). The CC33 and CCS3 polymorphisms were observed in significant linkage disequilibrium (D' = 0.91, r2 = 0.72). Haplotype frequencies were significantly different in BPAD patients than in controls (p = 0.03), with a significant over-transmission of the 'TG' haplotype in BPAD patients (p = 0.001).
We suggest that the PPP3CC gene might be a susceptibility gene for BPAD, in accordance with current neurobiological hypotheses that implicate dysregulation of signal-transduction pathways, such as those regulated by calcineurin, in the etiology of affective disorders.
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