Ankyrin-2, also known as Ankyrin-B, and Brain ankyrin, is a
protein which in humans is encoded by the ANK2gene.[2][3] Ankyrin-2 is ubiquitously expressed, but shows high expression in
cardiac muscle. Ankyrin-2 plays an essential role in the localization and membrane stabilization of ion transporters and
ion channels in
cardiomyocytes, as well as in
costamere structures. Mutations in ANK2 cause a dominantly-inherited, cardiac
arrhythmia syndrome known as
long QT syndrome 4[4] as well as
sick sinus syndrome; mutations have also been associated to a lesser degree with
hypertrophic cardiomyopathy. Alterations in ankyrin-2 expression levels are observed in human
heart failure.
Structure
Ankyrin-B protein is around 220 kDa, with several isoforms.[5] The ANK2 gene is approximately 560 kb in size and consists of 53 exons on human chromosome 4; ANK2 is also transcriptionally regulated via over 30
alternative splicing events with variable expression of
isoforms in
cardiac muscle.[6][7][8] Ankyrin-B is a member of the
ankyrin family of proteins, and is a modular
protein which is composed of three structural domains: an
N-terminal domain containing multiple
ankyrin repeats; a central region with a highly conserved spectrin binding domain and death domain; and a
C-terminal regulatory domain which is the least conserved and subject to variation, and determines ankyrin-B activity.[2][9][10] The membrane-binding region of ankyrin-B is composed of 24 consecutive
ankyrin repeats, and it is the membrane-binding domain of ankyrins that confer functional differences among ankyrin
isoforms.[10] Though ubiquitously expressed, ankyrin-B shows high expression levels in
cardiac muscle, and is expressed 10-fold lower levels in
skeletal muscle, suggesting that ankyrin-B plays a specifically adapted functional role in
cardiac muscle.[11]
Function
Ankyrin-B is a member of the
ankyrin family of proteins.
Ankyrin-1 has been shown to be essential in normal function of erythrocytes;[12] however, ankyrin-B and
ankyrin-3 play essential roles in the localization and membrane stabilization of ion transporters and
ion channels in
cardiomyocytes.[11][13]
Mutations in the ANK2gene have been associated with a dominantly-inherited, cardiac
arrhythmia syndrome known as long QT syndrome, type 4, [4] also known as ankyrin-B syndrome which can be described as an atypical arrhythmia syndrome with
bradycardia,
atrial fibrillation,
conduction block, arrhythmia and risk of
sudden cardiac death.[26][27][28] Intense investigation has been carried out regarding the linking of ANK2 mutations to the range of severity of cardiac phenotypes, and initial evidence suggests that the varying degrees of loss of function of ankyrin-B may explain the effect of any particular mutation.[29][30][31][32][33][34][35][36][37][38]
Initially, a
Glu1425
Gly mutation in ANK2 was found to cause dominantly-inherited
long QT syndrome type 4, cardiac
arrhythmia. The mechanistic underpinnings of this mutation include abnormal expression and targeting of the sodium pump, the
sodium-calcium exchanger, and
inositol-1,4,5-trisphosphate receptors to
transverse tubules, as well as
calcium handling resulting in
extrasystoles.[39] Further analysis in ANK2 mutations localized in the regulatory domain of ankyrin-2, which is specific to the ankyrin-2 isoform, indicated that
long QT syndrome was not a consistent clinical manifestation of ANK2 mutations;[40] however, the effect on Ca(2+) dynamics and localization/expression of the
sodium calcium exchanger,
sodium potassium ATPase and
inositol triphosphate receptor in
cardiomyocytes were consistent observations. This study demonstrated that common pathogenic features of all ANK2 mutations was the abnormal coordination of a panel of related
ion channels and transporters.[41] Additional mechanistic studies have shown that atrial
cardiomyocytes lacking ankyrin-B have shortened
action potentials, which can be explained by decreased
voltage-dependent calcium channel expression, specifically Ca(v)1.3, which is responsible for low voltage-activated L-type Ca(2+) currents. Ankyrin-B directly associates with and is required for targeting Ca(v)1.3 to membranes.[42]
ANK2 mutations have also been identified in patients with
sinus node dysfunction. Mechanistic studies on effects of these mutations in mice showed severe
bradycardia and variability in
heart rate, as well as dysfunction in ankyrin-B-based trafficking pathways in primary and subsidiary pacemaker cells.[43][44][45] In a large genotype-phenotype study of 874 patients with
hypertrophic cardiomyopathy, patients with ANK2 variants exhibited greater maximum left
ventricular wall thickness.[46]
In patients with both
ischemic and non-ischemic heart failure, ankyrin-B levels are altered. Further mechanistic study showed that
reactive oxygen species, intracellular
calcium and
calpain regulate cardiac ankyrin-B levels, and ankyrin-B is required for normal cardioprotection following
ischemia reperfusion injury.[47]
^Zhang T, Moss A, Cong P, Pan M, Chang B, Zheng L, Fang Q, Zareba W, Robinson J, Lin C, Li Z, Wei J, Zeng Q, Long QT International Registry I, HVP-China I, Qi M (November 2010).
"LQTS gene LOVD database". Human Mutation. 31 (11): E1801–10.
doi:
10.1002/humu.21341.
PMC3037562.
PMID20809527.
^Robaei D, Ford T, Ooi SY (February 2015). "Ankyrin-B syndrome: a case of sinus node dysfunction, atrial fibrillation and prolonged QT in a young adult". Heart, Lung & Circulation. 24 (2): e31–4.
doi:
10.1016/j.hlc.2014.09.013.
PMID25456501.
^Mohler PJ, Schott JJ, Gramolini AO, Dilly KW, Guatimosim S, duBell WH, Song LS, Haurogné K, Kyndt F, Ali ME, Rogers TB, Lederer WJ, Escande D, Le Marec H, Bennett V (February 2003). "Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death". Nature. 421 (6923): 634–9.
Bibcode:
2003Natur.421..634M.
doi:
10.1038/nature01335.
PMID12571597.
S2CID4429278.
^Sherman J, Tester DJ, Ackerman MJ (November 2005). "Targeted mutational analysis of ankyrin-B in 541 consecutive, unrelated patients referred for long QT syndrome genetic testing and 200 healthy subjects". Heart Rhythm. 2 (11): 1218–23.
doi:
10.1016/j.hrthm.2005.07.026.
PMID16253912.