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

A. J. Huq, M.D. Pertile, A. M. Davis, H. Landon, P. A. James, C. F. Kline, J. Vohra, P. J. Mohler, M.B. Delatycki

Research output: Contribution to journalArticleOtherpeer-review

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)612-618
Number of pages7
JournalHeart Lung and Circulation
Volume26
Issue number6
DOIs
Publication statusPublished - 1 Jun 2017
Externally publishedYes

Keywords

  • ANK2
  • Ankyrin-B
  • Ankyrin-B syndrome
  • Cardiac arrhythmia
  • Chromosome 4 translocation
  • Long QT syndrome type 4

Cite this