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Other entities represented in this entry:
SNOMEDCT: 764457005; ORPHA: 101016, 768; DO: 0111700; MONDO: 0010958;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q25-q26 | Cardiac arrhythmia, ankyrin-B-related | 600919 | Autosomal dominant | 3 | ANK2 | 106410 |
| 4q25-q26 | Long QT syndrome 4 | 600919 | Autosomal dominant | 3 | ANK2 | 106410 |
A number sign (#) is used with this entry because a cardiac arrhythmia syndrome with variable manifestations can be caused by heterozygous mutation in the ankyrin-B gene (ANK2; 106410) on chromosome 4q25-q26.
Long QT syndrome-4 can also be caused by mutation in the ANK2 gene. For a general phenotypic description and a discussion of genetic heterogeneity of long QT syndrome, see 192500.
Loss-of-function mutations in ANK2 can result in a broad spectrum of clinical cardiac phenotypes. Carriers of some mutations (e.g., E1425G, 106410.0001) display QT interval prolongation, stress- and/or exercise-induced polymorphic ventricular arrhythmia, syncope, and sudden cardiac death. Patients with other variants show clinical phenotypes, sometimes mild, extending beyond LQTS, leading to the label 'ankyrin-B syndrome.' These phenotypes include bradycardia, sinus arrhythmia, delayed conduction/conduction block, idiopathic ventricular fibrillation, and catecholaminergic polymorphic ventricular tachycardia (Mohler et al., 2007).
Long QT Syndrome 4
Schott et al. (1995) reported a large French family segregating a form of long QT syndrome. Among 25 affected members (21 adults and 4 children), the average rate-corrected QT interval was 490 ms (for adults) and 465 ms (for children) compared with 380 ms and 403 ms in unaffected individuals. Sinus node bradycardia or junctional escape rhythm was diagnosed in all patients with LQT4. Episodes of atrial fibrillation were diagnosed in 12 adult patients but were absent during childhood. Since the initial description, Mohler et al. (2003) reported that 8 additional individuals had been born, of whom 4 carried the LQT4 haplotype. Sinus node abnormalities were diagnosed in utero in all affected members from generation 4.
Ankyrin-B Syndrome
Mohler et al. (2004) expanded the phenotype of the disorder originally called LQT4 by Schott et al. (1995). They found that 8 unrelated patients with loss of ankyrin-B activity displayed varying degrees of cardiac dysfunction, including bradycardia, sinus arrhythmia, idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, and risk of sudden death. 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.
In a 65-member family in which the long QT syndrome was associated with more marked sinus bradycardia than usual, leading to sinus node dysfunction, Schott et al. (1995) excluded linkage to 3 previously mapped LQT loci on chromosomes 11 (LQT1; 192500), 7 (LQT2; 613688), and 3 (LQT3; 603830). Positive linkage was obtained for markers located on 4q25-q27, with a maximum lod score of 7.05 for marker D4S402.
Mohler et al. (2003) sequenced the ankyrin-B gene, which was known to map to the 4q25-q27 region, and identified an A-to-G transition at position 4274 in exon 36, resulting in a glu1425-to-gly substitution (E1425G; 106410.0001), in a patient with long QT syndrome-4.
Mohler et al. (2004) identified 8 unrelated probands harboring 5 different ankyrin-B loss-of-function mutations (106410.0001-106410.0005), 4 of which were previously undescribed, whose clinical features distinguished the cardiac phenotype from classic long QT syndromes. The mutations were localized in the ankyrin-B regulatory domain, which distinguishes function of ankyrin-B from ankyrin-G (ANK3; 600465) in cardiomyocytes.
Mohler et al. (2007) identified 7 novel nonsynonymous variants in ANK2 in patients with a variety of cardiac phenotypes. Four of these variants displayed abnormal activity in cardiomyocytes.
Splawski (2004) suggested the designation 'sick sinus syndrome associated with bradycardia' for this disorder.
Mohler et al. (2003) reported that mice heterozygous for a null mutation in ankyrin-B were haploinsufficient and displayed arrhythmia similar to humans. Analysis of ECGs and heart rates of unrestrained animals using implanted radiotransmitter electrodes revealed significant similarities in cardiac phenotype between humans with LQT4 and AnkB +/- mice. AnkB +/- mice displayed bradycardia, heart rate variability, and sudden cardiac death. The mutation in ankyrin-B resulted in disruption in the cellular organization of the sodium pump, the sodium/calcium exchanger, and inositol-1,4,5-triphosphate receptors (all ankyrin-B-binding proteins), which reduced the targeting of these proteins to the transverse tubules as well as reducing overall protein level. Ankyrin-B mutation also led to altered calcium ion signaling in adult cardiomyocytes that resulted in extrasystoles, and provided a rationale for the arrhythmia. Thus, Mohler et al. (2003) identified a novel mechanism for cardiac arrhythmia due to abnormal coordination of multiple functionally related ion channels and transporters.
In transfection assays in neonatal mouse cardiomyocytes, Mohler et al. (2007) found that disease-associated human ANK2 mutations caused a range of in vitro phenotypes, with those variants demonstrating the most severe loss of function correlating with the most severe human phenotype. They identified 3 distinct functional classes of ANK2 loss-of-function variants.
Mohler, P. J., Le Scouarnec, S., Denjoy, I., Loew, J. S., Guicheney, P., Caron, L., Driskell, I. M., Schott, J.-J., Norris, K., Leenhardt, A., Kim, R. B., Escande, D., Roden, D. M. Defining the cellular phenotype of 'ankyrin-B syndrome' variants. Circulation 115: 432-441, 2007. [PubMed: 17242276] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.106.656512]
Mohler, P. J., Schott, J.-J., Gramolini, A. O., Dilly, K. W., Guatimosim, S., duBell, W. H., Song, L.-S., Haurogne, K., Kyndt, F., Ali, M. E., Rogers, T. B., Lederer, W. J., Escande, D., Le Marec, H., Bennett, V. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature 421: 634-639, 2003. [PubMed: 12571597] [Full Text: https://doi.org/10.1038/nature01335]
Mohler, P. J., Splawski, I., Napolitano, C., Bottelli, G., Sharpe, L., Timothy, K., Priori, S. G., Keating, M. T., Bennett, V. A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. Proc. Nat. Acad. Sci. 101: 9137-9142, 2004. [PubMed: 15178757] [Full Text: https://doi.org/10.1073/pnas.0402546101]
Schott, J.-J., Charpentier, F., Peltier, S., Foley, P., Drouin, E., Bouhour, J.-B., Donnelly, P., Vergnaud, G., Bachner, L., Moisan, J.-P., Le Marec, H., Pascal, O. Mapping of a gene for long QT syndrome to chromosome 4q25-27. Am. J. Hum. Genet. 57: 1114-1122, 1995. [PubMed: 7485162]
Splawski, I. Personal Communication. Boston, Mass. 7/26/2004.