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Gene Review

Ank2  -  ankyrin 2, brain

Mus musculus

Synonyms: 100043364, AI835472, ANK-2, AW491075, Ank-2, ...
 
 
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Disease relevance of Ank2

  • Mutations of ankyrin-B cause a newly defined cardiac arrhythmia syndrome associated with abnormal calcium homeostasis in a mouse model [1].
  • Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death [2].
  • Ankyrin-B mutation also leads to altered Ca2+ signalling in adult cardiomyocytes that results in extrasystoles, and provides a rationale for the arrhythmia [2].
  • This report describes a congenital myopathy and major loss of thymic lymphocytes in ankyrin-B (-/-) mice as well as dramatic alterations in intracellular localization of key components of the Ca(2+) homeostasis machinery in ankyrin-B (-/-) striated muscle and thymus [3].
  • However, a prolonged rate-corrected QT interval was not a consistent feature, indicating that ankyrin-B dysfunction represents a clinical entity distinct from classic long QT syndromes [4].
 

Psychiatry related information on Ank2

 

High impact information on Ank2

  • Mice heterozygous for a null mutation in ankyrin-B are haploinsufficient and display arrhythmia similar to humans [2].
  • Mutation of ankyrin-B results in disruption in the cellular organization of the sodium pump, the sodium/calcium exchanger, and inositol-1,4,5-trisphosphate receptors (all ankyrin-B-binding proteins), which reduces the targeting of these proteins to the transverse tubules as well as reducing overall protein level [2].
  • The sarcoplasmic reticulum (SR) and SR/T-tubule junctions are apparently preserved in a normal distribution in ankyrin-B (-/-) skeletal muscle based on electron microscopy and the presence of a normal pattern of triadin and dihydropyridine receptor [3].
  • Extrapolation of these observations suggests defective targeting as the basis for abnormal localization of ryanodine receptors, IP3 receptors and SERCA in heart, and of IP3 receptors in the thymus of ankyrin-B (-/-) mice [3].
  • These data provide the first evidence of a physiological requirement for ankyrin-B in intracellular targeting of the calcium homeostasis machinery of striated muscle and immune system, and moreover, support a catalytic role that does not involve permanent stoichiometric complexes between ankyrin-B and targeted proteins [3].
 

Biological context of Ank2

  • Ank-2 maps to Chromosome 3 and its expression is unaffected by the nb mutation [6].
  • Here we report the identification of eight unrelated probands harboring ankyrin-B loss-of-function mutations, including four previously undescribed mutations, whose clinical features distinguish the cardiac phenotype associated with loss of ankyrin-B activity from classic long QT syndromes [4].
  • Alanine-scanning mutagenesis revealed that residues 1773, 1777, 1780, 1784, and 1788 located in a patch on one surface the helix are critical for ankyrin-B function in cardiomyocytes [7].
 

Anatomical context of Ank2

 

Associations of Ank2 with chemical compounds

  • However, both mutant forms of ankyrin-B are still capable of restoring inositol 1,4,5-trisphosphate receptor localization and normal contraction frequency of cardiomyocytes [9].
  • All mutations abolish ability of ankyrin-B to restore abnormal Ca(2+) dynamics and abnormal localization and expression of Na/Ca exchanger, Na/K ATPase, and InsP(3)R in ankyrin-B(+/-) cardiomyocytes [4].
  • 220-kDa ankyrin-B is required for coordinated assembly of Na/Ca exchanger, Na/K ATPase, and inositol trisphosphate (InsP(3)) receptor at transverse-tubule/sarcoplasmic reticulum sites in cardiomyocytes [4].

References

  1. Ankyrin-based cardiac arrhythmias: a new class of channelopathies due to loss of cellular targeting. Mohler, P.J., Bennett, V. Curr. Opin. Cardiol. (2005) [Pubmed]
  2. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Mohler, P.J., Schott, J.J., Gramolini, A.O., Dilly, K.W., Guatimosim, S., duBell, W.H., Song, L.S., Haurogné, K., Kyndt, F., Ali, M.E., Rogers, T.B., Lederer, W.J., Escande, D., Le Marec, H., Bennett, V. Nature (2003) [Pubmed]
  3. Ankyrin-B is required for intracellular sorting of structurally diverse Ca2+ homeostasis proteins. Tuvia, S., Buhusi, M., Davis, L., Reedy, M., Bennett, V. J. Cell Biol. (1999) [Pubmed]
  4. A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. Mohler, P.J., Splawski, I., Napolitano, C., Bottelli, G., Sharpe, L., Timothy, K., Priori, S.G., Keating, M.T., Bennett, V. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  5. Physiological roles of axonal ankyrins in survival of premyelinated axons and localization of voltage-gated sodium channels. Bennett, V., Lambert, S. J. Neurocytol. (1999) [Pubmed]
  6. Purkinje cell degeneration associated with erythroid ankyrin deficiency in nb/nb mice. Peters, L.L., Birkenmeier, C.S., Bronson, R.T., White, R.A., Lux, S.E., Otto, E., Bennett, V., Higgins, A., Barker, J.E. J. Cell Biol. (1991) [Pubmed]
  7. Isoform specificity among ankyrins. An amphipathic alpha-helix in the divergent regulatory domain of ankyrin-b interacts with the molecular co-chaperone Hdj1/Hsp40. Mohler, P.J., Hoffman, J.A., Davis, J.Q., Abdi, K.M., Kim, C.R., Jones, S.K., Davis, L.H., Roberts, K.F., Bennett, V. J. Biol. Chem. (2004) [Pubmed]
  8. Distinct fetal Ank-1 and Ank-2 related proteins and mRNAs in normal and nb/nb mice. Peters, L.L., Turtzo, L.C., Birkenmeier, C.S., Barker, J.E. Blood (1993) [Pubmed]
  9. Ankyrin-B targets beta2-spectrin to an intracellular compartment in neonatal cardiomyocytes. Mohler, P.J., Yoon, W., Bennett, V. J. Biol. Chem. (2004) [Pubmed]
 
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