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ank3

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Official Full Name
ankyrin 3, node of Ranvier (ankyrin G)
Background
Ankyrins are a family of proteins that are believed to link the integral membrane proteins to the underlying spectrin-actin cytoskeleton and play key roles in activities such as cell motility, activation, proliferation, contact, and the maintenance of specialized membrane domains. Multiple isoforms of ankyrin with different affinities for various target proteins are expressed in a tissue-specific, developmentally regulated manner. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation. Ankyrin 3 is an immunologically distinct gene product from ankyrins 1 and 2, and was originally found at the axonal initial segment and nodes of Ranvier of neurons in the central and peripheral nervous systems. Multiple transcript variants encoding different isoforms have been found for this gene.
Synonyms
ANK3; ANKYRIN-G; ankyrin-3; ankyrin G119; ankyrin 3, node of Ranvier (ankyrin G); ankyrin-3, node of Ranvier; FLJ45464; OTTHUMP00000019653; OTTHUMP00000019656; OT-THUMP00000217458; OTTHUMP00000217575; CHANK3

The Ankyrin-G protein encoded by the ANK3 gene functions to immobilize the backbone protein on the cell membrane. As an important linker protein, ankyrin plays an important role in a variety of biological activities. Recent studies have found that ankyrin may be involved in cell signal transduction and apoptosis, and participate in several key links in the process of signal transduction. At the same time, a number of genome-wide association studies (GWAS) in recent years have also suggested that the ANK3 gene and its encoded ankyrin are closely related to mental diseases, especially schizophrenia, and bipolar disorder.

ANK3 and Bipolar Disorder

Bipolar disorder is a psychiatric disorder characterized by manic episodes and depression, and its pathogenesis is not yet clear. In recent years, a variety of factors with complex functions and located upstream of the regulatory mechanism have become research hotspots, such as brain-derived nerve growth factor (BDNF) and Ankyrin-G. In a number of GWAS studies on the two-way affective disorder, it was also found that ANK3 gene single nucleotide polymorphism sites (SNPs) rs10994336, rs1938526, and rs10994415 were associated with the disease. Therefore, the role of the ANK3 gene in the pathogenesis of bipolar disorder has received more attention.

The scientists then used molecular genetics techniques to conduct a more in-depth study of the gene. The association of two variant sites of ANK gene with bipolar disorder was repeated to verify the rs10994336 locus found by GWAS. A meta-analysis was used to further demonstrate that the ANK3 gene may be a risk gene for bipolar disorder. Ament et al. found that the gene may affect the excitability of neurons through rare mutations, thereby increasing the risk of bipolar disorder. Although a large number of studies have repeatedly verified that several sites discovered by GWAS are closely related to the onset of bipolar disorder, the specific biological mechanism remains unclear. Subsequently, at the transcriptional level, after silencing the expression of ANK3 gene, the initial segment of the axon of the nerve cell disappears and is replaced by a dendritic structure, which may be the basis for brain structural changes in patients with the bipolar disorder caused by ANK3 gene.

Figure 1. Model of the molecular signature of (A) BD-related pathophysiology and (B) lithium׳s mechanism of action in Ank3+/− mice. (Gottschalk, et al. 2017).

Bavamian's other study on small RNA (microRNA) found that enhanced miR-34a expression regulates ANK3 and CACNB3 genes and impairs neural differentiation, synaptic protein expression, and neuromorphology, thereby reducing endogenous miR- 34a expression and enhancing the evolution of dendrites. It further illustrates the molecular regulation mechanism of ANK3 gene triggering brain structural changes in bipolar disorder.

With the development of brain imaging technology, scientists have carried out imaging studies of brain structures and functions related to this gene. Subsequently, Delvecchio et al. repeated the above two SNPs of ANK3 in patients with bipolar disorder and healthy people. Study on the clinical symptoms, carrying the risk allele of the people of Hamilton Depression Scale (HDRS), Young Mania Rating Scale (YMRS) and Brief Psychiatric Rating Scale (BPRS) scores were higher than those in healthy controls. In the cognitive function assessment, the above two alleles did not affect the general intelligence and response time scores of different groups. In imaging, healthy individuals with the rs10994336 risk allele showed reduced activity in the lateral temporal cortex and the middle and lower temporal cortex in the white matter-related activity test. In contrast, in the healthy individuals carrying the rs9804190 risk allele, the activity of the lateral prefrontal cortex and the mid-media and the inferior frontal increased.

ANK3 and Major Depressive Disorder

Experiments have shown that glutamatergic synapses are inextricably linked to the occurrence of a variety of neuropsychiatric diseases. The loss of synapses and the decrease in their plasticity are more inseparable from the onset of affective disorders. At the same time, through the study of the hippocampus in patients with post-mortem depression, the regulation of glutamate-related genes on synapses was also found. With the development and application of technologies such as RNA interference, gene knockout, and superresolution imaging, Smith et al. discovered the regulation of ANK3 on glutamatergic synaptic structure and function. Thus, it is proved that the ANK3 gene may be associated with the onset of depressive disorder. However, at present, the research on ANK3 gene and major depressive disorder is rarely reported.

Frazier et al. selected gene SNPs with high correlations between synaptic function and affective disease: ANK3 (rs10994336), BDNF (rs6265), CACNA1C (rs1006737) and DGKH (rs1170191) for clinical symptoms, cognitive function levels, and brain imaging research. No positive results associated with the ANK3 gene were found. Although there are few studies on the role of ANK3 gene in the pathogenesis of depressive disorder, the relationship between ANK3 and major depressive disorder is worthy of further investigation due to the important role of Ankyrin-G in signal transduction, neurogenesis, and synaptic plasticity.

References:

  1. Ament, S. A., Szelinger, S., Glusman, G., Ashworth, J., Hou, L., & Akula, N., et al. (2015). Rare variants in neuronal excitability genes influence risk for bipolar disorder. Proceedings of the National Academy of Sciences of the United States of America, 112(11), 3576.
  2. Bavamian, S., Mellios, N., Lalonde, J., Fass, D. M., Wang, J., & Sheridan, S. D., et al. (2015). Dysregulation of mir-34a links neuronal development to genetic risk factors for bipolar disorder. Molecular Psychiatry, 20(5), 573-84.
  3. Hiroaki, H., Noriko, Y., Toshiya, T., Miho, O., Takashi, F., & Daimei, S., et al. (2014). Cognitive effects of the ank3 risk variants in patients with bipolar disorder and healthy individuals. Journal of Affective Disorders, 158(158), 90-96.
  4. Delvecchio, G., Dima, D., & Frangou, S. (2015). The effect of ank3 bipolar-risk polymorphisms on the working memory circuitry differs between loci and according to risk-status for bipolar disorder. American Journal of Medical Genetics Part B Neuropsychiatric Genetics, 168(3), 188-196.
  5. Smith, K. R., Kopeikina, K. J., Fawcettpatel, J. M., Leaderbrand, K., Gao, R., & Schürmann, B., et al. (2014). Psychiatric risk factor ank3/ankyrin-g nanodomains regulate the structure and function of glutamatergic synapses. Neuron, 84(2), 399-415.
  6. Frazier, T. W., Youngstrom, E. A., Frankel, B. A., Zunta‐Soares, G. B., Sanches, M., & Escamilla, M., et al. (2014). Candidate gene associations with mood disorder, cognitive vulnerability, and fronto‐limbic volumes. Brain & Behavior, 4(3), 418-30.
  7. Gottschalk, M. G., Leussis, M. P., Ruland, T., Gjeluci, K., Petryshen, T. L., & Bahn, S. (2017). Lithium reverses behavioral and axonal transport-related changes associated with ank3 bipolar disorder gene disruption. European Neuropsychopharmacology the Journal of the European College of Neuropsychopharmacology, 27(3).