Theprotein encoded by this gene, ankyrin-3 is an immunologically distinct gene product from ankyrinsANK1 andANK2, and was originally found at theaxonal initial segment andnodes of Ranvier ofneurons in the central and peripheral nervous systems. Alternatively spliced variants may be expressed in other tissues. Although multiple transcript variants encoding several different isoforms have been found for this gene, the full-length nature of only two have been characterized.[5]
Within the nervous system, ankyrin-G is specifically localized to theneuromuscular junction, the axon initial segment and theNodes of Ranvier.[7] Within the nodes of Ranvier whereaction potentials are actively propagated, ankyrin-G has long been thought to be the intermediate binding partner toneurofascin and voltage-gatedsodium channels.[8] The genetic deletion of ankyrin-G from multiple neuron types has shown that ankyrin-G is required for the normal clustering of voltage-gatedsodium channels at theaxon hillock and foraction potential firing.[9][10]
The ANK3 protein associates with the cardiac sodium channelNav1.5 (SCN5A). Both proteins are highly expressed at ventricular intercalated disc and T-tubule membranes incardiomyocytes. A mutation in the Nav1.5 protein blocks interaction with ANK3 binding and therefore disrupts surface expression of Nav1.5 in cardiomyocytes resulting inBrugada syndrome, a type of cardiacarrhythmia.[11]
The protein encoded by the ANK3 gene is a member of theankyrin family of proteins that link the integral membrane proteins to the underlyingspectrin-actincytoskeleton. Ankyrins play key roles in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains. 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.[5]
^Kapfhamer D, Miller DE, Lambert S, Bennett V, Glover TW, Burmeister M (May 1995). "Chromosomal localization of the ankyrinG gene (ANK3/Ank3) to human 10q21 and mouse 10".Genomics.27 (1):189–191.doi:10.1006/geno.1995.1023.PMID7665168.
Weimer JM, Chattopadhyay S, Custer AW, Pearce DA (May 2005). "Elevation of Hook1 in a disease model of Batten disease does not affect a novel interaction between Ankyrin G and Hook1".Biochemical and Biophysical Research Communications.330 (4):1176–1181.doi:10.1016/j.bbrc.2005.03.103.PMID15823567.
Shirahata E, Iwasaki H, Takagi M, Lin C, Bennett V, Okamura Y, et al. (September 2006). "Ankyrin-G regulates inactivation gating of the neuronal sodium channel, Nav1.6".Journal of Neurophysiology.96 (3):1347–1357.doi:10.1152/jn.01264.2005.PMID16775201.
Morgan AR, Turic D, Jehu L, Hamilton G, Hollingworth P, Moskvina V, et al. (September 2007). "Association studies of 23 positional/functional candidate genes on chromosome 10 in late-onset Alzheimer's disease".American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics.144B (6):762–770.doi:10.1002/ajmg.b.30509.PMID17373700.S2CID26081707.
Morgan AR, Hamilton G, Turic D, Jehu L, Harold D, Abraham R, et al. (September 2008). "Association analysis of 528 intra-genic SNPs in a region of chromosome 10 linked to late onset Alzheimer's disease".American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics.147B (6):727–731.doi:10.1002/ajmg.b.30670.PMID18163421.S2CID13916214.
