Ankyrin 3: genetic association with bipolar disorder and relevance to disease pathophysiologyReport as inadecuate

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Biology of Mood and Anxiety Disorders

, 2:18

The genetic basis of mood and anxiety disorders


Bipolar disorder BD is a multi-factorial disorder caused by genetic and environmental influences. It has a large genetic component, with heritability estimated between 59-93%. Recent genome-wide association studies GWAS using large BD patient populations have identified a number of genes with strong statistical evidence for association with susceptibility for BD. Among the most significant and replicated genes is ankyrin 3 ANK3, a large gene that encodes multiple isoforms of the ankyrin G protein. This article reviews the current evidence for genetic association of ANK3 with BD, followed by a comprehensive overview of the known biology of the ankyrin G protein, focusing on its neural functions and their potential relevance to BD. Ankyrin G is a scaffold protein that is known to have many essential functions in the brain, although the mechanism by which it contributes to BD is unknown. These functions include organizational roles for subcellular domains in neurons including the axon initial segment and nodes of Ranvier, through which ankyrin G orchestrates the localization of key ion channels and GABAergic presynaptic terminals, as well as creating a diffusion barrier that limits transport into the axon and helps define axo-dendritic polarity. Ankyrin G is postulated to have similar structural and organizational roles at synaptic terminals. Finally, ankyrin G is implicated in both neurogenesis and neuroprotection. ANK3 and other BD risk genes participate in some of the same biological pathways and neural processes that highlight several mechanisms by which they may contribute to BD pathophysiology. Biological investigation in cellular and animal model systems will be critical for elucidating the mechanism through which ANK3 confers risk of BD. This knowledge is expected to lead to a better understanding of the brain abnormalities contributing to BD symptoms, and to potentially identify new targets for treatment and intervention approaches.

KeywordsAnkyrin G Bipolar disorder Schizophrenia Genome-wide association study GWAS Axon initial segment Nodes of Ranvier GABA Neurogenesis Synapse AbbreviationsAISAxon initial segment

ANK3Ankyrin 3

BDBipolar disorder

CACNA1CCalcium channel voltage-dependent, L type, alpha 1C subunit

CNSCentral nervous system

CPG2Candidate plasticity gene 2

DCLK3Doublecortin-like kinase 3

DGKHDiacylglycerol kinase eta

GWASGenome-wide association study


LMAN2LLectin mannose-binding 2-like


NMJNeuromuscular junction

NoRNodes of Ranvier

ODZ4Odz odd Oz-ten-m homolog 4 Drosophila

PGCPsychiatric GWAS Consortium

PTGFRThe prostaglandin F receptor gene

SNPSingle nucleotide polymorphism

SYNE1Spectrin repeat containing nuclear envelope 1

TRANK1Tetratricopeptide repeat and ankyrin repeat containing 1.

Electronic supplementary materialThe online version of this article doi:10.1186-2045-5380-2-18 contains supplementary material, which is available to authorized users.

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Author: Melanie P Leussis - Jon M Madison - Tracey L Petryshen


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