Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Sep;13(9):1932-40.
doi: 10.1016/j.hrthm.2016.06.012. Epub 2016 Jun 11.

Common Human ANK2 Variant Confers in Vivo Arrhythmia Phenotypes


Common Human ANK2 Variant Confers in Vivo Arrhythmia Phenotypes

Hassan Musa et al. Heart Rhythm. .


Background: Human ANK2 (ankyrin-B) loss-of-function variants are directly linked with arrhythmia phenotypes. However, in atypical non-ion channel arrhythmia genes such as ANK2 that lack the same degree of robust structure/function and clinical data, it may be more difficult to assign variant disease risk based simply on variant location, minor allele frequency, and/or predictive structural algorithms. The human ankyrin-B p.L1622I variant found in arrhythmia probands displays significant diversity in minor allele frequency across populations.

Objective: The objective of this study was to directly test the in vivo impact of ankyrin-B p.L1622I on cardiac electrical phenotypes and arrhythmia risk using a new animal model.

Methods: We tested arrhythmia phenotypes in a new "knock-in" animal model harboring the human ankyrin-B p.L1622I variant.

Results: Ankyrin-B p.L1622I displays reduced posttranslational expression in vivo, resulting in reduced cardiac ankyrin-B expression and reduced association with binding-partner Na/Ca exchanger. Ankyrin-B(L1622I/L1622I) mice display changes in heart rate, atrioventricular and intraventricular conduction, and alterations in repolarization. Furthermore, ankyrin-B(L1622I/L1622I) mice display catecholamine-dependent arrhythmias. At the cellular level, ankyrin-B(L1622I/L1622I) myocytes display increased action potential duration and severe arrhythmogenic afterdepolarizations that provide a mechanistic rationale for the arrhythmias.

Conclusion: Our findings support in vivo arrhythmogenic phenotypes of an ANK2 variant with unusual frequency in select populations. On the basis of our findings and current clinical data, we support classification of p.L1622I as a "mild" loss-of-function variant that may confer arrhythmia susceptibility in the context of secondary risk factors including environment, medication, and/or additional genetic variation.

Keywords: Ankyrin; Arrhythmia; Ion channel; Mouse models of disease; Myocyte.

Similar articles

See all similar articles

Cited by 5 articles

  • Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy.
    Roberts JD, Murphy NP, Hamilton RM, Lubbers ER, James CA, Kline CF, Gollob MH, Krahn AD, Sturm AC, Musa H, El-Refaey M, Koenig S, Aneq MÅ, Hoorntje ET, Graw SL, Davies RW, Rafiq MA, Koopmann TT, Aafaqi S, Fatah M, Chiasson DA, Taylor MR, Simmons SL, Han M, van Opbergen CJ, Wold LE, Sinagra G, Mittal K, Tichnell C, Murray B, Codima A, Nazer B, Nguyen DT, Marcus FI, Sobriera N, Lodder EM, van den Berg MP, Spears DA, Robinson JF, Ursell PC, Green AK, Skanes AC, Tang AS, Gardner MJ, Hegele RA, van Veen TA, Wilde AA, Healey JS, Janssen PM, Mestroni L, van Tintelen JP, Calkins H, Judge DP, Hund TJ, Scheinman MM, Mohler PJ. Roberts JD, et al. J Clin Invest. 2019 Jul 2;129(8):3171-3184. doi: 10.1172/JCI125538. eCollection 2019 Jul 2. J Clin Invest. 2019. PMID: 31264976 Free PMC article.
  • Defining new mechanistic roles for αII spectrin in cardiac function.
    Lubbers ER, Murphy NP, Musa H, Huang CY, Gupta R, Price MV, Han M, Daoud E, Gratz D, El Refaey M, Xu X, Hoeflinger NK, Friel EL, Lancione P, Wallace MJ, Cavus O, Simmons SL, Williams JL, Skaf M, Koenig SN, Janssen PML, Rasband MN, Hund TJ, Mohler PJ. Lubbers ER, et al. J Biol Chem. 2019 Jun 14;294(24):9576-9591. doi: 10.1074/jbc.RA119.007714. Epub 2019 May 7. J Biol Chem. 2019. PMID: 31064843
  • Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation.
    Zhu W, Wang C, Hu J, Wan R, Yu J, Xie J, Ma J, Guo L, Ge J, Qiu Y, Chen L, Liu H, Yan X, Liu X, Ye J, He W, Shen Y, Wang C, Mohler PJ, Hong K. Zhu W, et al. Circulation. 2018 Dec 4;138(23):2682-2697. doi: 10.1161/CIRCULATIONAHA.118.034541. Circulation. 2018. PMID: 30571258 Free PMC article.
  • Novel Mechanistic Roles for Ankyrin-G in Cardiac Remodeling and Heart Failure.
    Makara MA, Curran J, Lubbers ER, Murphy NP, Little SC, Musa H, Smith SA, Unudurthi SD, Rajaram MVS, Janssen PML, Boyden PA, Bradley EA, Hund TJ, Mohler PJ. Makara MA, et al. JACC Basic Transl Sci. 2018 Nov 12;3(5):675-689. doi: 10.1016/j.jacbts.2018.07.008. eCollection 2018 Oct. JACC Basic Transl Sci. 2018. PMID: 30456339 Free PMC article.
  • The evolving role of ankyrin-B in cardiovascular disease.
    Koenig SN, Mohler PJ. Koenig SN, et al. Heart Rhythm. 2017 Dec;14(12):1884-1889. doi: 10.1016/j.hrthm.2017.07.032. Epub 2017 Jul 29. Heart Rhythm. 2017. PMID: 28765088 Free PMC article. Review.

Publication types

LinkOut - more resources