Original ArticleA Novel Mechanism for Human Cardiac Ankyrin-B Syndrome due to Reciprocal Chromosomal Translocation
Introduction
The regulation of the cardiac action potential is a highly coordinated event, mediated by the spatio-temporal expression and function of numerous ion channels, pumps, and accessory proteins. Precise physiological activity of cardiac ion channels and transporters is tightly regulated by the defined biophysical characteristics, expression, and localisation properties of those proteins within the specific cardiomyocyte membrane domains. Within the last two decades, the role of the ankyrin family of coordinating proteins has been more fully elucidated, giving rise to new loci for cardiac arrhythmia syndromes. Ankyrins are a family of cytoskeletal adaptor molecules with both structural and modulatory roles in the cardiac myocyte. Specifically, ankyrins localise and regulate a number of cardiac ion channels to specialised membrane domains. Loss-of-function variants in ANK2 (ankyrin-B), have been demonstrated to underlie the “ankyrin-B syndrome”, a multi-faceted spectrum of cardiac dysfunction phenotypes, including bradycardia, sinus node dysfunction, atrial fibrillation, prolonged QT interval and predisposition to torsades de pointes and sudden cardiac death [1]. It is notable that to date, ANK2-linked disease has been limited to single ‘point mutations’ [2].
ANK2 is one of three similar, yet distinct ankyrin genes (ANK1, ANK2, and ANK3). ANK2 is located on the long arm of chromosome 4 (4q25-q26) [3]. A number of ANK2 human variants have been identified [4]. Here, we report a family with the unexpected finding of an ANK2 transection in chromosome 4. Specifically, the proband has a balanced translocation between the long arms of chromosomes 4 and 9. In vitro work with lymphoblasts isolated from an affected individual demonstrate a decrease in ankyrin-B expression, along with significant decreases in the expression of known ankyrin-B binding partners. Furthermore, we describe the cardiac phenotypes in a number of family members with the translocation. Finally, we discuss an approach to cardiac screening in this family.
Section snippets
Ethics Committee Approval
Approval for this study was obtained from the Royal Children's Hospital Human Research Ethics Committee (HREC project number 28097).
Chromosomal Karyotype and Microarray Analysis
Conventional G-banded chromosome analysis on 72 hr synchronised peripheral blood lymphocyte cultures was carried out using standard cytogenetic techniques. Microarray analysis was carried out on DNA isolated from chorionic villi obtained from products of conception. Initial analysis was undertaken on NimbleGen Multiplex 135K v2.0 CGH array (Roche, Australia) using
Discussion
Reciprocal chromosome translocations occur due to recombination errors in the meiotic phase of cell division and can generate balanced and unbalanced gametes. Unbalanced gametes can result in miscarriage or a surviving child often with polymalformation and intellectual disability. Children who inherit the balanced translocation unaltered from a parent generally do not have increased rates of phenotypic impact as the overall genetic material is no different to the normal parent cell [7].
Funding
NIH Grants HL083422 HL084583; American Heart Association
Disclosures
The authors declare no conflicts of interest.
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