Alternative titles; symbols
HGNC Approved Gene Symbol: ANK3
Cytogenetic location: 10q21.2 Genomic coordinates (GRCh38): 10:60,026,298-60,733,528 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q21.2 | Intellectual developmental disorder, autosomal recessive 37 | 615493 | Autosomal recessive | 3 |
Ankyrins are peripheral membrane proteins thought to interconnect integral proteins with the spectrin-based membrane skeleton (summary by Kordeli and Bennett, 1991).
The ANK3 gene encodes ankyrin-G, which is located mainly at the nodes of Ranvier and the axon initial segment (AIS), 2 subcompartments of neurons responsible for the generation of action potentials. It has been shown to associate with the voltage-dependent sodium channel (summary by Iqbal et al., 2013).
Erythrocytic ankyrin, also known as ankyrin-R (ANK1; 612641), and brain ankyrin, also known as ankyrin-B or ankyrin-2 (ANK2; 106410), are distinct forms.
Kordeli and Bennett (1991) concluded that the ankyrin isoform present at the node of Ranvier was the product of a previously unidentified ankyrin gene, as ankyrin was still present in the node of Ranvier in ankyrin-R-deficient mice (carrying the nb mutation) and was not recognized by antibodies specific for ankyrin-B or ankyrin-R.
Kordeli et al. (1995) described the cDNA sequence of a third ankyrin gene with alternatively spliced isoforms expressed in brain as well as a variety of other tissues. The 2 largest protein isoforms, which contain an unusual serine-rich sequence, are expressed only in nervous tissue. Specific antibodies raised against this serine-rich sequence stained AIS and nodes of Ranvier in cryosections from the rat brain. The full-length polypeptide has a molecular mass of 480 kD and includes a globular head domain, with membrane- and spectrin-binding activities, as well as an extended 'tail' domain. Kordeli et al. (1995) termed the gene ankyrin-G, based on its giant size and general expression. The 2 brain-specific isoforms were of sizes 480 and 270 kD.
Kloth et al. (2017) noted that there are 3 major isoforms of ANK3 in the brain, 190-kD, 270-kD, and 480-kD, each of which shows a tissue-specific distribution pattern. The isoforms are responsible for different functions in neuronal circuits.
Using GABAergic cell type-specific promoters and mouse BACs, Ango et al. (2004) generated BAC transgenic mice with fluorescence-labeled Purkinje cells and interneurons visible at synaptic resolution during cerebellar development. They found that basket axons always contacted Purkinje soma before innervating Purkinje AIS and prior to the formation of elaborate pinceau synapses. This synapse-targeting process followed the establishment of a subcellular gradient of neurofascin-186 (NF186), an alternatively spliced form of neurofascin (609145) (Davis et al., 1996), along the Purkinje AIS-soma axis. The gradient was dependent on ankyrin-G, an AIS-restricted membrane adaptor protein that recruits NF186. In the absence of the NF186 gradient, basket axons lost directional growth along Purkinje neurons and precisely followed NF186 to ectopic locations. Disruption of NF186-ankyrin-G interactions at AIS reduced pinceau synapse formation.
Using coimmunoprecipitation experiments, Mohler et al. (2004) demonstrated that the 190-kD ankyrin-G isoform in adult rat heart associates with the cardiac sodium channel Na(v)1.5, the gene product of the SCN5A gene (600163). By confocal microscopy they showed that ankyrin-G, like Na(v)1.5, is highly expressed at ventricular intercalated disc and T-tubule membranes in cardiomyocytes. Mohler et al. (2004) presented evidence that a human mutation in the SCN5A gene (600163.0033) blocks ankyrin-G binding and disrupts surface expression of Na(v)1.5 in cardiomyocytes, resulting in Brugada syndrome (601144), a dominantly inherited cardiac arrhythmia.
Kizhatil et al. (2009) found that targeting of cyclic nucleotide-gated (CNG) channels to the rod outer segment required their interaction with ankyrin-G. Ankyrin-G localized exclusively to rod outer segments, coimmunoprecipitated with the CNG channel, and bound to the C-terminal domain of the channel beta-1 subunit (CNGB1; 600724). Ankyrin-G depletion in neonatal mouse retinas markedly reduced CNG channel expression. Transgenic expression of CNG channel beta-subunit mutants in Xenopus rods showed that ankyrin-G binding was necessary and sufficient for targeting of the beta-1 subunit to outer segments. Thus, Kizhatil et al. (2009) concluded that ankyrin-G is required for transport of CNG channels to the plasma membrane of rod outer segments.
By fluorescence in situ hybridization, Kapfhamer et al. (1995) mapped the ANK3 gene to 10q21. By intersubspecific backcross analysis, they mapped the murine homolog to mouse chromosome 10 between microsatellite marker D10Mit31 and the Bcr gene. This interval of mouse chromosome 10 is known to comprise a region with homology of synteny to human 10q. The localization of ANK3 may help identify neurologic disorders associated with the gene in man or mouse.
Iqbal et al. (2013) reported a boy with autism, attention deficit-hyperactivity disorder (ADHD), cognitive problems, and sleep disorder associated with a balanced translocation with breakpoints between chromosomes 2q11.2 and 10q21.2. The breakpoint on 10q21.2 mapped to intron 30 of the ANK3 gene and interrupted all ANK3 transcript variants; the breakpoint on 2q11.2 was in a pseudogene. Patient cells showed significantly decreased expression of the ANK3 gene, about 25% compared to controls. The patient had mildly delayed development, delayed speech, and behavioral abnormalities, including aggression. He had a peculiar facial appearance, with mildly upslanted palpebral fissures, broad nose, and flat philtrum. He also had 2 sacral dimples and several patches of depigmented skin.
In 3 Pakistani sibs, born of consanguineous parents, with autosomal recessive intellectual developmental disorder-37 (MRT37; 615493) and behavioral abnormalities, Iqbal et al. (2013) identified a homozygous frameshift mutation in the ANK3 gene (600465.0001). The mutation, which was found by homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Iqbal et al. (2013) concluded that ANK3 mutations and polymorphisms are associated with a wide spectrum of mental disorders presenting in a continuum from mental retardation to autism.
In 2 affected members of a consanguineous Persian family (family M312) with MRT37, Hu et al. (2019) identified a homozygous frameshift mutation in the ANK3 gene (600465.0004). The variant was found by exome sequencing and confirmed by Sanger sequencing. The family was part of a large cohort of 404 consanguineous families, mostly Iranian, in which 2 or more offspring had impaired intellectual development. Functional studies of the variant and studies of patient cells were not performed.
Sobotzik et al. (2009) demonstrated that targeted depletion of the AnkG gene in mouse cerebellum caused axons to develop protrusions that closely resembled dendritic spines. These mutant spines were enriched in postsynaptic proteins and lacked typical ultrastructural features of the axon initial segment, such as cytoplasmic bundles of microtubules. These axonal spines were contacted by presynaptic glutamatergic boutons, consistent with features of dendrites. The findings indicated that loss of AnkG causes a disruption in axo-dendritic polarity.
Iqbal et al. (2013) found that targeted knockdown of the Drosophila Ank2 gene, which is the homolog of human ANK3, at the neuromuscular junction resulted in small synapses and less synaptic boutons compared to controls. There was a reduction in synapse area and length. Ablation of Ank2 gene in the mushroom bodies, the learning and memory center of the fly, caused a reduction in short-term memory despite normal learning and normal motor function. The findings suggested a specific cognitive defect.
In 3 Pakistani sibs, born of consanguineous parents, with autosomal recessive intellectual developmental disorder-37 (MRT37; 615493) and behavioral abnormalities, Iqbal et al. (2013) identified a homozygous 1-bp deletion (c.10995delC) in the ANK3 gene, resulting in a frameshift and premature termination in exon 42 (Thr3666LeufsTer2). Exon 42 is unique to the largest isoform of ANK2, and the mutation was predicted to specifically affect synthesis of the 270/480-kD isoforms, which are brain-specific. The mutant mRNA was likely targeted for nonsense-mediated mRNA decay, but no patient cells were available for testing. The mutation, which was found by homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes, or Exome Sequencing Project databases, or in 268 ethnically matched controls or 200 Danish exomes.
This variant is classified as a variant of unknown significance because its contribution to the development of autism (see 209850) has not been confirmed.
In a patient with autism, Bi et al. (2012) identified a de novo heterozygous c.4705T-G transversion in exon 42 of the ANK3 gene, resulting in a ser1569-to-ala (S1569A) substitution at a highly conserved residue. The variant was identified by whole-exome sequencing and confirmed by Sanger sequencing. It was not found in the dbSNP or 1000 Genomes Project databases, or in 2,000 Caucasian exomes. This patient was ascertained from a cohort of 20 patients with autism spectrum disorder who underwent whole-exome sequencing. Another patient with a de novo heterozygous S1569A substitution was subsequently found in a cohort of 47 patients with autism spectrum disorder who underwent direct sequencing of the ANK3 gene. Two more patients from the second cohort carried heterozygous missense variants in the ANK3 gene (T3720M and T4255P, respectively) that were not present in 2,000 Caucasian exomes, but each of these variants was also present in an unaffected parent. Bi et al. (2012) suggested that the role of ANK3 at synapses in the central nervous system make it a candidate gene for susceptibility to autism. No functional studies were performed.
This variant is classified as a variant of unknown significance because its contribution to the development of autism (see 209850) has not been confirmed.
In an 8-year-old boy with impaired intellectual development (IQ of 77), speech impairment, and autistic features, Kloth et al. (2017) identified a de novo heterozygous c.1990G-T transversion (c.1990G-T, NM_020987.3) in exon 17 of the ANK3 gene, resulting in a gly664-to-ter (G664X) substitution in the N-terminal ankyrin repeat domain. The mutation, which was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 139), 1000 Genomes Project, or ExAC databases. It was predicted to affect all 3 isoforms of the ANK3 gene, likely activating nonsense-mediated mRNA decay and causing haploinsufficiency. However, functional studies of the variant and studies of patient cells were not performed. Additional clinical features in the patient included macrocephaly (+3.7 SD), macrosomia, chronic hunger, altered sleep pattern, and ADHD.
In 2 affected members of a consanguineous Persian family (family M312) with autosomal recessive intellectual developmental disorder-37 (MRT37; 615493), Hu et al. (2019) identified a homozygous 1-bp deletion (c.11033del, NM_020987) in the ANK3 gene, predicted to result in a frameshift and premature termination (Pro3678LeufsTer45). The variant was found by exome sequencing and confirmed by Sanger sequencing. The family was part of a large cohort of 404 consanguineous families, mostly Iranian, in which 2 or more offspring had impaired intellectual development. Functional studies of the variant and studies of patient cells were not performed.
Ango, F., di Cristo, G., Higashiyama, H., Bennett, V., Wu, P., Huang, Z. J. Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at Purkinje axon initial segment. Cell 119: 257-272, 2004. [PubMed: 15479642] [Full Text: https://doi.org/10.1016/j.cell.2004.10.004]
Bi, C., Wu, J., Jiang, T., Liu, Q., Cai, W., Yu, P., Cai, T., Zhao, M., Jiang, Y., Sun, Z. S. Mutations of ANK3 identified by exome sequencing are associated with autism susceptibility. Hum. Mutat. 33: 1635-1638, 2012. [PubMed: 22865819] [Full Text: https://doi.org/10.1002/humu.22174]
Davis, J. Q., Lambert, S., Bennett, V. Molecular composition of the node of Ranvier: identification of ankyrin-binding cell adhesion molecules neurofascin (mucin+/third FNIII domain-) and NrCAM at nodal axon segments. J. Cell Biol. 135: 1355-1367, 1996. [PubMed: 8947556] [Full Text: https://doi.org/10.1083/jcb.135.5.1355]
Hu, H., Kahrizi, K., Musante, L., Fattahi, Z., Herwig, R., Hosseini, M., Oppitz, C., Abedini, S. S., Suckow, V., Larti, F., Beheshtian, M., Lipkowitz, B. Genetics of intellectual disability in consanguineous families. Molec. Psychiat. 24: 1027-1039, 2019. [PubMed: 29302074] [Full Text: https://doi.org/10.1038/s41380-017-0012-2]
Iqbal, Z., Vandeweyer, G., van der Voet, M., Waryah, A. M., Zahoor, M. Y., Besseling, J. A., Roca, L. T., Vulto-van Silfhout, A. T., Nijhof, B., Kramer, J. M., Van der Aa, N., Ansar, M., and 11 others. Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders. Hum. Molec. Genet. 22: 1960-1970, 2013. [PubMed: 23390136] [Full Text: https://doi.org/10.1093/hmg/ddt043]
Kapfhamer, D., Miller, D. E., Lambert, S., Bennett, V., Glover, T. W., Burmeister, M. Chromosomal localization of the ankyrin-G gene (ANK3/Ank3) to human 10q21 and mouse 10. Genomics 27: 189-191, 1995. [PubMed: 7665168] [Full Text: https://doi.org/10.1006/geno.1995.1023]
Kizhatil, K., Baker, S. A., Arshavsky, V. Y., Bennett, V. Ankyrin-G promotes cyclic nucleotide-gated channel transport to rod photoreceptor sensory cilia. Science 323: 1614-1617, 2009. [PubMed: 19299621] [Full Text: https://doi.org/10.1126/science.1169789]
Kloth, K., Denecke, J., Hempel, M., Johannsen, J., Strom, T. M., Kubisch, C., Lessel, D. First de novo ANK3 nonsense mutation in a boy with intellectual disability, speech impairment and autistic features. Europ. J. Med. Genet. 60: 494-498, 2017. [PubMed: 28687526] [Full Text: https://doi.org/10.1016/j.ejmg.2017.07.001]
Kordeli, E., Bennett, V. Distinct ankyrin isoforms at neuron cell bodies and nodes of Ranvier resolved using erythrocyte ankyrin-deficient mice. J. Cell Biol. 114: 1243-1259, 1991. [PubMed: 1832678] [Full Text: https://doi.org/10.1083/jcb.114.6.1243]
Kordeli, E., Lambert, S., Bennett, V. Ankyrin-G: a new ankyrin gene with neural-specific isoforms localized at the axonal initial segment and node of Ranvier. J. Biol. Chem. 270: 2352-2359, 1995. [PubMed: 7836469] [Full Text: https://doi.org/10.1074/jbc.270.5.2352]
Mohler, P. J., Rivolta, I., Napolitano, C., LeMaillet, G., Lambert, S., Priori, S. G., Bennett, V. Na(v)1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Na(v)1.5 on the surface of cardiomyocytes. Proc. Nat. Acad. Sci. 101: 17533-17538, 2004. [PubMed: 15579534] [Full Text: https://doi.org/10.1073/pnas.0403711101]
Sobotzik, J.-M., Sie, J. M., Politi, C., Del Turco, D., Bennett, V., Deller, T., Schultz, C. AnkyrinG is required to maintain axo-dendritic polarity in vivo. Proc. Nat. Acad. Sci. 106: 17564-17569, 2009. [PubMed: 19805144] [Full Text: https://doi.org/10.1073/pnas.0909267106]