title: A rare mutation of CACNA1C in a patient with bipolar disorder, and decreased gene expression associated with a bipolar-associated common SNP of CACNA1C in brain.
abstract: Timothy Syndrome (TS) is caused by very rare exonic mutations of the CACNA1C gene that produce delayed inactivation of Cav1.2 voltage-gated calcium channels during cellular action potentials, with greatly increased influx of calcium into the activated cells. The major clinical feature of this syndrome is a long QT interval that results in cardiac arrhythmias. However, TS also includes cognitive impairment, autism and major developmental delays in many of the patients. We observed the appearance of bipolar disorder (BD) in a patient with a previously reported case of TS, who is one of the very few patients to survive childhood. This is most interesting because the common single-nucleotide polymorphism (SNP) most highly associated with BD is rs1006737, which we show here is a cis-expression quantitative trait locus for CACNA1C in human cerebellum, and the risk allele (A) is associated with decreased expression. To combine the CACNA1C perturbations in the presence of BD in this patient and in patients with the common CACNA1C SNP risk allele, we would propose that either increase or decrease in calcium influx in excitable cells can be associated with BD. In treatment of BD with calcium channel blocking drugs, we would predict better response in patients without the risk allele, because they have increased CACNA1C expression.
authors: Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
authors: E S
authors: ES
authors: Gershon
authors: Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
authors: K
authors: K
authors: Grennan
authors: Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
authors: J
authors: J
authors: Busnello
authors: Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
authors: J A
authors: JA
authors: Badner
authors: Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
authors: F
authors: F
authors: Ovsiew
authors: Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL, USA.
authors: S
authors: S
authors: Memon
authors: Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
authors: N
authors: N
authors: Alliey-Rodriguez
authors: Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
authors: J
authors: J
authors: Cooper
authors: Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA.
authors: B
authors: B
authors: Romanos
authors: 1] Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA [2] The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors: C
authors: C
authors: Liu
mesh_terms: D000328:Adult; D001321:Autistic Disorder; D001714:Bipolar Disorder / Q000150:complications / Q000235:genetics*; D001921:Brain / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000096:biosynthesis / Q000235:genetics*; D002531:Cerebellum / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics*; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008133:Long QT Syndrome / Q000150:complications / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D010296:Parietal Lobe / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics; D013576:Syndactyly / Q000150:complications / Q000235:genetics
chemical_list: C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type
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