Original Article
A Novel Mechanism for Human Cardiac Ankyrin-B Syndrome due to Reciprocal Chromosomal Translocation

https://doi.org/10.1016/j.hlc.2016.09.013Get rights and content

Background

Cardiac rhythm abnormalities are a leading cause of morbidity and mortality in developed countries. Loss-of-function variants in the ANK2 gene can cause a variety of cardiac rhythm abnormalities including sinus node dysfunction, atrial fibrillation and ventricular arrhythmias (called the “ankyrin-B syndrome”). ANK2 encodes ankyrin-B, a molecule critical for the membrane targeting of key cardiac ion channels, transporters, and signalling proteins.

Methods and Results

Here, we describe a family with a reciprocal chromosomal translocation between chromosomes 4q25 and 9q26 that transects the ANK2 gene on chromosome 4 resulting in loss-of-function of ankyrin-B. Select family members with ankyrin-B haploinsufficiency due to the translocation displayed clinical features of ankyrin-B syndrome. Furthermore, evaluation of primary lymphoblasts from a carrier of the translocation showed altered levels of ankyrin-B as well as a reduced expression of downstream ankyrin-binding partners.

Conclusions

Thus, our data conclude that, similar to previously described ANK2 loss-of-function “point mutations”, large chromosomal translocations resulting in ANK2 haploinsufficiency are sufficient to cause the human cardiac ankyrin-B syndrome. The unexpected ascertainment of ANK2 dysfunction via the discovery of a chromosomal translocation in this family, the determination of the familial phenotype, as well as the complexities in formulating screening and treatment strategies are discussed.

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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