Mechanisms underlying the role of ankyrin-B in cardiac and neurological health and disease

Abstract

The ANK2 gene encodes for ankyrin-B (ANKB), one of 3 members of the ankyrin family of proteins, whose name is derived from the Greek word for anchor. ANKB was originally identified in the brain (B denotes “brain”) but has become most widely known for its role in cardiomyocytes as a scaffolding protein for ion channels and transporters, as well as an interacting protein for structural and signaling proteins. Certain loss-of-function ANK2 variants are associated with a primarily cardiac-presenting autosomal-dominant condition with incomplete penetrance and variable expressivity characterized by a predisposition to supraventricular and ventricular arrhythmias, arrhythmogenic cardiomyopathy, congenital and adult-onset structural heart disease, and sudden death. Another independent group of ANK2 variants are associated with increased risk for distinct neurological phenotypes, including epilepsy and autism spectrum disorders. The mechanisms underlying ANKB's roles in cells in health and disease are not fully understood; however, several clues from a range of molecular and cell biological studies have emerged. Notably, ANKB exhibits several isoforms that have different cell-type–, tissue–, and developmental stage– expression profiles. Given the conservation within ankyrins across evolution, model organism studies have enabled the discovery of several ankyrin roles that could shed important light on ANKB protein-protein interactions in heart and brain cells related to the regulation of cellular polarity, organization, calcium homeostasis, and glucose and fat metabolism. Along with this accumulation of evidence suggesting a diversity of important ANKB cellular functions, there is an on-going debate on the role of ANKB in disease. We currently have limited understanding of how these cellular functions link to disease risk. To this end, this review will examine evidence for the cellular roles of ANKB and the potential contribution of ANKB functional variants to disease risk and presentation. This contribution will highlight the impact of ANKB dysfunction on cardiac and neuronal cells and the significance of understanding the role of ANKB variants in disease.

Single-cell transcriptomics identifies a p21-activated kinase important for survival of the zoonotic parasiteFasciola hepatica

“…Related to these terms are for example the neuropilin and tolloid protein (D915_000810), which has been found in neurons as well as a type of smooth muscle cells in humans 61 and functions in the neuromuscular junction in Drosophila melanogaster 62 , or two genes enocoding for ankyrin 2 (D915_000071, D915_002954), which contain an ankyrin repeat region. The family of ankyrins is involved in the attachment of membrane proteins to the cytoskeleton, and especially type 2 ankyrins have been shown to function in muscle cells 63,64 .…”

Detection of a de novo heterozygous ANK2 variant in a child with autism spectrum disorder and epilepsy: a case report

“…It is vastly recognized in current literature that lossof-function variants in ANK2 can result in a broad spectrum of clinical cardiac phenotypes including Long QT syndrome 4 and Ankyrin-B Syndrome (OMIM: 600919) [6]. According to animal model experiments, ANK2 encodes an ankyrin protein involved in synaptic stability.…”

“…Due to its interactions with the voltage-gated Ca V 2.1 calcium channel, ANK2 variants had been associated to occurrence of seizures [8]. Recently, ANK2 gene has also been linked to the etiology of ASD [4][5][6]. However, this gene is currently not associated with neurodevelopmental disorders in the Online Mendelian Inheritance in Man (OMIM) database.…”

“…Next-generation sequencing technologies have greatly enhanced the identification of new genes associated with ASD. Recently, ANK2 gene has also been pointed out as a candidate gene for the etiology of ASD [4][5][6].…”