Alternative titles; symbols
HGNC Approved Gene Symbol: ANK2
SNOMEDCT: 764457005;
Cytogenetic location: 4q25-q26 Genomic coordinates (GRCh38): 4:112,705,622-113,383,736 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q25-q26 | Cardiac arrhythmia, ankyrin-B-related | 600919 | Autosomal dominant | 3 |
| Long QT syndrome 4 | 600919 | Autosomal dominant | 3 |
Tse et al. (1991) studied immunoreactive isoforms of erythrocyte ankyrin found in nonerythroid tissues. Using an erythrocyte ankyrin cDNA clone as a hybridization probe, they isolated a clone from a human genomic library that hybridized at low but not at high stringency. Further studies suggested that the clone represented part of a gene for nonerythroid ankyrin, which they designated ANK2.
Otto et al. (1991) isolated and sequenced cDNAs related to 2 brain ankyrin isoforms and showed that they are produced through alternative splicing of the mRNA from a single gene.
The ANK2 gene contains 46 exons (Mohler et al., 2007). Exon 38 is brain-specific.
The axon initial segment (AIS) is the site at which neural signals arise, and should be the most efficient site to regulate neural activity. Kuba et al. (2010) reported that deprivation of auditory input in an avian brainstem auditory neuron leads to an increase in AIS length, thus augmenting the excitability of the neuron. The length of the AIS, defined by the distribution of voltage-gated sodium channels and the AIS anchoring protein, ankyrin G, increased by 1.7 times in 7 days after auditory input deprivation. This was accompanied by an increase in the whole-cell sodium current, membrane excitability, and spontaneous firing. Kuba et al. (2010) concluded that their work demonstrated homeostatic regulations of the AIS, which may contribute to the maintenance of the auditory pathway after hearing loss. Furthermore, plasticity at the spike initiation site suggests a powerful pathway for refining neuronal computation in the face of strong sensory deprivation.
By analysis of somatic cell hybrids and by fluorescence in situ hybridization, Tse et al. (1991) assigned the ANK2 gene to 4q25-q27.
By analysis of human/rodent cell hybrids, Otto et al. (1991) assigned the brain ankyrin gene to chromosome 4.
Cardiac Phenotypes
Schott et al. (1995) characterized a large French kindred with long QT syndrome associated with sinus node dysfunction and episodes of atrial fibrillation segregating as an autosomal dominant trait. They mapped the disorder to an 18-cM interval on 4q25-q27 (LQT4; 600919). Mohler et al. (2003) sequenced the ANK2 gene, which maps to the same region, and identified a glu1425-to-gly (E1425G) missense mutation (106410.0001). Ankyrin-B appears to be the first identified protein to be implicated in a congenital long QT syndrome that is not an ion channel or channel subunit.
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, and expanded the phenotype previously described by Schott et al. (1995). Mohler et al. (2004) found that humans with ankyrin-B mutations display 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. The mutations were localized in the ankyrin-B regulatory domain, which distinguishes function of ankyrin-B from ankyrin-G (ANK3; 600465) in cardiomyocytes. All mutations abolished ability of ankyrin-B to restore abnormal Ca(2+) dynamics and abnormal localization and expression of Na/Ca exchanger, Na/K ATPase, and InsP3 receptor in ankyrin-B +/- cardiomyocytes. This study, considered together with the first description of ankyrin-B mutations associated with cardiac dysfunction (Mohler et al., 2003), supported a previously undescribed paradigm for human disease due to abnormal coordination of multiple functionally related ion channels and transporters, in this case the Na/K ATPase, Na/Ca exchanger, and InsP3 receptor.
Mohler et al. (2007) identified 4 previously undescribed ANK2 variants resulting in cardiac dysfunction. They presented the first description of differences in cellular phenotypes conferred by specific ANK2 variants, and proposed that the various degrees of ankyrin-B loss of function contribute to the range of severity of cardiac dysfunction. They concluded that their data identified ANK2 variants as modulators of human arrhythmias, provided the first insight into the clinical spectrum of 'ankyrin-B syndrome,' and reinforced the role of ankyrin-B-dependent protein interactions in regulating cardiac electrogenesis.
Associations Pending Confirmation
Guissart et al. (2023) identified a de novo mutation in the ANK2 gene in a 17-year-old patient who had mild developmental delay at age 2 years. At age 17, he had severe autism, anxiety, a mood disorder, and poor verbal communication. He also had tall stature, macrocephaly, and increased body weight. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was a c.285+1G-T transversion (c.285+1G-T, NM_001148.6) affecting the splice donor site of intron 3. It was predicted to result in an in-frame deletion of 33 amino acids (Asn63_Lys95del) and to affect the long and short ANK2 isoforms.
Tuvia et al. (1999) found that ankyrin-B -/- mice were born in mendelian ratios but had 70 to 80% mortality on postnatal day 1, and 100% mortality by postnatal day 21. Mortality was due to musculoskeletal defects and neonatal myopathy, as well as defects in immune and nervous systems. Ankyrin-B -/- neonatal cardiomyocytes showed abnormal Ca(2+) homeostasis during spontaneous contractions compared with wildtype. Loss of ankyrin-B resulted in abnormal sorting and localization of Serca1 (ATP2A1; 108730) and ryanodine receptor-1 (RYR; 180901) in cardiomyocytes and skeletal muscle, leading to defects in Ca(2+) homeostasis. Inositol 1,4,5-triphosphate (IP3) receptors (e.g., ITPR1; 147265), which are responsible for intracellular Ca(2+) release, were also abnormally localized in cardiomyocytes and thymus of ankyrin-B -/- mice, and they exhibited reduced accumulation compared with wildtype.
Mohler et al. (2003) reported that mice heterozygous for a null mutation in ankyrin-B were haploinsufficient and displayed arrhythmia similar to humans. The mutation in ankyrin-B resulted in disruption in the cellular organization of the sodium pump, the sodium/calcium exchanger, and IP3 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 a large French kindred with autosomal dominant type 4 long QT syndrome (600919), Mohler et al. (2003) demonstrated that the underlying defect is a glu1425-to-gly (E1425G) missense mutation in ankyrin-B. The amino acid substitution was the result of an A-to-G transition at nucleotide position 4274 in exon 36 of the ANK2 gene.
Further studies reported by Mohler et al. (2004) expanded the phenotype associated with this mutation (see 600919). In a screening of 664 patients for mutations in the ANK2 gene, a Caucasian female was found to carry the E1425G mutation. She was clinically unaffected and, in contrast to previously identified E1425G patients (Mohler et al., 2003), had a normal QTc of 410 msec with a heart rate of 60 beats per minute. The proband's 67-year-old mother was a carrier of the E1425G variant with slightly elevated QTc (430-450 msec) and moderately low heart rate (63 beats per minute). Three sibs of the proband died young of sudden death at 25, 17, and 15 years of age. The 25-year-old died while winning a prize. The 17-year-old died in the shower and had previously experienced syncopal episodes associated with athletics. The 15-year-old died getting out of the pool after swimming. The E1425G mutation was not observed in 550 control individuals. It was the only SSCP variant identified within the ankyrin-B spectrin-binding domain (exons 24-36).
In 2 unrelated Caucasian probands from the United States with marginally elevated QTc and arrhythmia (600919), Mohler et al. (2004) identified a 4877C-A transversion in exon 42 of the ANK2 gene, resulting in a thr1626-to-asn (T1626N) substitution. One proband was a 46-year-old female who had a QTc of 450 msec and had experienced syncope, but had a normal resting heart rate of 72 beats per minute. Her daughter was also heterozygous for the T1626N mutation and died of sudden death at age 19 years with no previous cardiac symptoms; QTc and heart rate data were not available. Two sibs, 2 sons, and the mother of the proband were also carriers of the mutation and had resting QTc in the normal range. At the time of report, these carriers were asymptomatic. The second proband was a 51-year-old male who displayed mildly elevated QTc (450 msec) with sinus arrhythmia (heart rate varying from 50 to 110 beats per minute). Two of his sibs with normal QTc were heterozygous for the T1626N mutation but asymptomatic at the time of report. The T1626N mutation was not observed in 550 control individuals.
In a European Caucasian female with ventricular tachycardia and ventricular fibrillation (600919), Mohler et al. (2004) identified a 4864C-A transversion in exon 42 of the ANK2 gene, resulting in a leu1622-to-ile (L1622I) substitution. The proband had a normal QTc and a resting heart rate of 63 beats per minute. The proband's mother, sister, and brother were carriers of the mutation, but at the time of report all had been asymptomatic with normal resting QTc and normal heart rates. The L1622I mutation was not observed in control individuals.
In 2 unrelated probands with long QT syndrome (LQT4; 600919), Mohler et al. (2004) identified a 5336C-T transition in exon 45 of the ANK2 gene, resulting in an arg1788-to-trp (R1788W) substitution. One proband was a 37-year-old Caucasian female from the United States. She presented with syncope (originally treated as a seizure) at age 12 years. This woman subsequently had multiple episodes of syncope associated with sleep, and torsades de pointes ventricular tachycardia was documented. Beta-blocker therapy failed to eliminate symptoms and she was treated with an implantable cardiac defibrillator. ECGs revealed a heart rate of 60 beats per minute, prominent T-U waves, and prolongation of the QT interval with a QTc of 530 msec. The proband's son had also been diagnosed with long QT syndrome. The second proband, heterozygous for the R1788W mutation, was a Caucasian female from Europe with multiple episodes of exercise-associated syncope. She presented with supraventricular and ventricular tachycardias that were reproducibly elicited by exercise tests. The patient had normal QTc at rest (430 msec), but prolongation of 470 msec was observed after a syncopal episode. The woman was successfully treated with beta blockers; however, exercise-induced nonsustained supraventricular and ventricular arrhythmias persisted. The father of the proband carried the mutation with QTc of 430 msec and a heart rate of 67 beats per minute. The R1788W mutation was not identified in 280 DNA samples obtained from individuals with normal ECG.
This variant, formerly titled CARDIAC ARRHYTHMIA, ANKYRIN-B-RELATED, has been reclassified because its contribution to the phenotype has not been confirmed.
In 2 unrelated probands with cardiac arrhythmia and ventricular fibrillation, respectively (600919), Mohler et al. (2004) identified a 5437G-A transition in exon 45 of the ANK2 gene, resulting in a glu1813-to-lys (E1813K) substitution. One proband was a 24-year-old Caucasian female from Europe diagnosed with recurring arrhythmia and documented torsades de pointes ventricular tachycardia. She presented with an elevated resting QTc of 490 msec and mild brachycardia (62 beats per minute). The second proband was a 60-year-old Caucasian male from the United States who displayed idiopathic ventricular fibrillation (Priori et al., 2001) with a normal QTc (395 msec), a normal resting ECG, and a heart rate of 64 beats per minute. The E1813K mutation was found in 5 DNA samples obtained from individuals with normal ECGs.
Guissart, C., Polge, A., Durand, N., Miret, A., Lumbroso, S., Francannet, C., Mouzat, K. Discovering the ANK2-related autism phenotype. Clin. Genet. 104: 384-386, 2023. [PubMed: 37088467] [Full Text: https://doi.org/10.1111/cge.14347]
Kuba, H., Oichi, Y., Ohmori, H. Presynaptic activity regulates Na+ channel distribution at the axon initial segment. Nature 465: 1075-1078, 2010. [PubMed: 20543825] [Full Text: https://doi.org/10.1038/nature09087]
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]
Otto, E., Kunimoto, M., McLaughlin, T., Bennett, V. Isolation and characterization of cDNAs encoding human brain ankyrins reveal a family of alternatively spliced genes. J. Cell Biol. 114: 241-253, 1991. [PubMed: 1830053] [Full Text: https://doi.org/10.1083/jcb.114.2.241]
Priori, S. G., Napolitano, C., Grillo, M. Concealed arrhythmogenic syndromes: the hidden substrate of idiopathic ventricular fibrillation? Cardiovasc. Res. 50: 218-223, 2001. [PubMed: 11334825] [Full Text: https://doi.org/10.1016/s0008-6363(01)00224-3]
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]
Tse, W. T., Menninger, J. C., Yang-Feng, T. L., Francke, U., Sahr, K. E., Lux, S. E., Ward, D. C., Forget, B. G. Isolation and chromosomal localization of a novel non-erythroid ankyrin gene. Genomics 10: 858-866, 1991. [PubMed: 1833308] [Full Text: https://doi.org/10.1016/0888-7543(91)90173-c]
Tuvia, S., Buhusi, M., Davis, L., Reedy, M., Bennett, V. Ankyrin-B is required for intracellular sorting of structurally diverse Ca(2+) homeostasis proteins. J. Cell Biol. 147: 995-1007, 1999. [PubMed: 10579720] [Full Text: https://doi.org/10.1083/jcb.147.5.995]