Ankyrin 3: genetic association with bipolar disorder and relevance to disease pathophysiology

Melanie P Leussis,Jon M Madison,Tracey L Petryshen

doi:10.1186/2045-5380-2-18

Abstract

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.

Highlights

Bipolar disorder (BD) is a multi-factorial disorder caused by genetic and environmental influences
It is possible that sequence variants in ankyrin 3 (ANK3) and Diacylglycerol kinase eta (DGKH) alter the functions of their encoded proteins in this pathway, disrupting downstream neural processes that lead to the emergence of BD symptoms, and that mood stabilizers mediate their clinical effect through normalizing pathway signaling
The ankyrin G protein encoded by ANK3 functions as a scaffold protein and adapter molecule between various membrane proteins and the inner membrane cytoskeleton

Summary

Introduction

Bipolar disorder (BD) is a multi-factorial disorder caused by genetic and environmental influences. There is solid evidence that, like antidepressant medications, some mood stabilizers increase adult neurogenesis in rodents in the hippocampus, one of two regions in the mature brain where new neurons are generated [11], suggesting a putative role of adult-born neurons in neural processes underlying BD.

Results

Conclusion