Alternative titles; symbols
HGNC Approved Gene Symbol: TANC2
Cytogenetic location: 17q23.2-q23.3 Genomic coordinates (GRCh38): 17:62,966,235-63,427,703 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q23.2-q23.3 | Intellectual developmental disorder with autistic features and language delay, with or without seizures | 618906 | Autosomal dominant | 3 |
The TANC2 gene encodes a synaptic scaffolding protein that interacts with other proteins at the postsynaptic density to regulate dendritic spines and excitatory synapse formation (summary by Guo et al., 2019).
By sequencing clones from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) obtained a partial TANC2 clone, which they designated KIAA1636. The transcript contains several repetitive elements in its 3-prime end. RT-PCR ELISA detected highest expression in whole adult brain, followed by testis and ovary. All other tissues, including fetal brain, showed much lower expression. Within specific adult brain regions, highest expression was detected in amygdala.
By database analysis, Han et al. (2010) identified full-length human TANC2, which encodes a 1,990-amino acid protein. TANC2 and TANC1 (611397) share 49.6% amino acid identity and have essentially the same domain structure, including ankyrin (see 612641) repeats, tetratricopeptide repeats, a coiled-coil domain, and a C-terminal PDZ-binding motif. In situ hybridization showed widespread expression of Tanc2 mRNA in rat brain, whereas Tanc1 mRNA was more concentrated in specific regions, including hippocampus, thalamus, and cerebellum. Western blot analysis of rat tissues revealed Tanc1 and Tanc2 protein expression in brain only. During rat brain development, Tanc2 protein was highly expressed at embryonic day-18 and gradually decreased to adult levels beginning in the third postnatal week. In contrast, Tanc1 protein expression was low during embryonic development and increased during the first 2 postnatal weeks.
Guo et al. (2019) stated that TANC2 is broadly expressed across many cells types in the developing human cerebral cortex, with enrichment in excitatory neurons and radial glia, in particular truncated and outer radial glia.
Hartz (2013) mapped the TANC2 gene to chromosome 17q23.3 based on an alignment of the TANC2 sequence (GenBank AB046856) with the genomic sequence (GRCh37).
Using various methods, Han et al. (2010) showed that human TANC1 and TANC2 interacted with PSD95 (DLG4; 602887) through their C-terminal PDZ-binding motifs in vitro and in vivo. TANC1 and TANC2 localized to dendritic spines in transfected rat hippocampal neurons in a manner that also required their C-terminal PDZ-binding motifs. Overexpression of human TANC1 and TANC2 in cultured rat neurons increased the density of dendritic spines and excitatory synapses.
Using a mass spectrometry approach, Stucchi et al. (2018) identified TANC2, liprin-alpha-2 (PPFIA2; 603143), and the calcium-binding protein calmodulin (see CALM1, 114180) as direct binding partners of KIF1A (601255), the primary motor protein for synaptic vesicles (SVs) and dense core vesicles (DCVs). Analysis with rat hippocampal neurons revealed that calcium enhanced Kif1a binding to DCVs and increased vesicle motility by acting through calmodulin. Tanc2 and liprin-alpha-2 were enriched in dendritic spines but were not part of the Kif1a cargo complex. Instead, they acted as postsynaptic density scaffolds to stop and capture Kif1a-bound DCVs upon dendritic spine entry. Knockdown experiments showed that depletion of Tanc2, Kif1a, or liprin-alpha-2 affected rat dendritic spine density and morphology. Moreover, nonsense mutations in human TANC2 associated with neuropsychiatric disorders (see MOLECULAR GENETICS) abolished interaction of TANC2 with KIF1A and affected recruitment of KIF1A-transported DCVs.
In 20 unrelated probands with intellectual developmental disorder with autistic features and language delay, with or without seizures (IDDALDS; 618906), Guo et al. (2019) identified heterozygous nonsense, frameshift, or splice site mutations, or intragenic deletions in the TANC2 gene (see, e.g., 615047.0001-615047.0006). The mutations, which were found by whole-exome sequencing, targeted sequencing, and array-based CGH, were confirmed by Sanger sequencing; none were present in the ExAC database. The patients were ascertained through a network of international collaborators and the GeneMatcher database. Eleven of the patients had de novo point mutations, and 5 probands inherited point mutations (from a mildly affected parent in 4 cases); the inheritance pattern could not be determined in 1 patient. Two affected sibs had an intragenic deletion inherited from their mosaic father, and 2 unrelated patients had de novo intragenic deletions. Functional studies of the variants and studies of patient cells were not performed, but the authors postulated a loss-of-function effect. Guo et al. (2019) also identified 5 unrelated individuals with overlapping phenotypes who were found to carry de novo heterozygous missense variants in the TANC2 gene. Three variants (R755H, R961Q, and H1689R) were found in 3 patients with a primary diagnosis of autism spectrum disorder. Another variant (R760C) was found in a patient with impaired intellect and speech delay (de Ligt et al., 2012), and the last (A794V) was found in a patient with schizophrenia (Fromer et al., 2014). The R755H, R760C, and A794V variants occurred in the ATPase regulatory domain, and R961Q was in 1 of the ANK domains. H1689R, R760C, and A794V and were not found in the ExAC nonpsychiatric samples, whereas R755H and R961Q were both reported 4 times in ExAC. Functional studies of these missense variants were not performed. All mutations occurred throughout the gene and there were no apparent genotype/phenotype correlations, although all the disruptive mutations occurred before the PDZ interacting motif.
Stucchi et al. (2018) found that the R760C and R1066X mutations abolished interaction of TANC2 with KIF1A, and that R760C affected recruitment of KIF1A-transported DCVs.
Guo et al. (2019) found that knockdown of the Tanc2 homolog 'rols' in Drosophila was embryonic lethal. In normal flies, the rols gene was expressed throughout the nervous system, in muscle cells during early development, and in the nuclei of wrapping glia at the neuromuscular junction (NMJ). Knockdown of rols disrupted the formation of the synapse and interfered with proper glutamate receptor clustering at the NMJ. Targeted knockdown of rols in Drosophila glial resulted in abnormal courting behavior with an increase in total duration of wing extension behavior compared to wildtype, whereas locomotion, grooming, and copulation were similar to wildtype. Notably, knockdown of rols in neuronal cells did not alter wing extension behaviors. The findings suggested a role for rols at the postsynaptic region and in glia that modulate behavior.
Han et al. (2010) found that deletion of Tanc2 in mice was embryonic lethal.
In a 7-year-old boy (family NN1) with intellectual developmental disorder with autistic features and language delay without seizures (IDDALDS; 618906), Guo et al. (2019) identified a de novo heterozygous c.4447C-T transition (c.4447C-T, NM_025185.3) in the TANC2 gene, resulting in a gln1483-to-ter (Q1483X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a loss-of-function effect of the mutation.
In a 12-year-old boy (family SS2) with intellectual developmental disorder with autistic features and language delay without seizures (IDDALDS; 618906), Guo et al. (2019) identified a heterozygous G-to-A transition (c.547+1G-A, NM_025185.3) in the TANC2 gene, predicted to result in a splice site alteration and disruption of the TANC2 protein. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database. The mutation was inherited from the patient's father, who had a complex neuropsychiatric diagnosis with bipolar disorder, ADHD, and PTSD. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a loss-of-function effect of the mutation.
In 2 unrelated patients (families HU1 and CC1) with intellectual developmental disorder with autistic features and language delay without seizures (IDDALDS; 618906), Guo et al. (2019) identified a de novo G-to-A transition (c.1219+1G-A, NM_025185.3) in the TANC2 gene predicted to result in a splice site alteration and disruption of the TANC2 protein. The mutation, which was found by exome sequencing or targeted sequencing and confirmed by Sanger sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a loss-of-function effect of the mutation.
In a 15-year-old boy (family SS1) with intellectual developmental disorder with autistic features and language delay without seizures (IDDALDS; 618906), Guo et al. (2019) identified a de novo heterozygous c.3196C-T transition (c.3196C-T, NM_025185.3) in the TANC2 gene, predicted to result in an arg1066-to-ter (R1066X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a loss-of-function effect of the mutation.
Stucchi et al. (2018) found that the R1066X mutation abolished interaction of TANC2 with KIF1A (601255).
In a 4-year-old girl (family LN) with intellectual developmental disorder with autistic features and language delay without seizures (IDDALDS; 618906), Guo et al. (2019) identified a de novo heterozygous 1-bp deletion (c.4449delG, NM_025185.3), predicted to result in a frameshift and premature termination (Gln1483HisfsTer69). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a loss-of-function effect of the mutation.
In a 14-year-old boy (family LG) with intellectual developmental disorder with autistic features and language delay with seizures (IDDALDS; 618906), Guo et al. (2019) identified a de novo heterozygous 1-bp deletion (c.4405delC, NM_025185.3) in the TANC2 gene, predicted to result in a frameshift and premature termination (Arg1469GlyfsTer6). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a loss-of-function effect of the mutation.
de Ligt, J., Willemsen, M. H., van Bon, B. W. M., Kleefstra, T., Yntema, H. G., Kroes, T., Vulto-van Silfhout, A. T., Koolen, D. A., de Vries, P., Gilissen, C., del Rosario, M., Hoischen, A., Scheffer, H., de Vries, B. B. A., Brunner, H. G., Veltman, J. A., Vissers, L. E. L. M. Diagnostic exome sequencing in persons with severe intellectual disability. New Eng. J. Med. 367: 1921-1929, 2012. [PubMed: 23033978] [Full Text: https://doi.org/10.1056/NEJMoa1206524]
Fromer, M., Pocklington, A. J., Kavanagh, D. H., Williams, H. J., Dwyer, S., Gormley, P., Georgieva, L., Rees, E., Palta, P., Ruderfer, D. M., Carrera, N., Humphreys, I., and 20 others. De novo mutations in schizophrenia implicate synaptic networks. Nature 506: 179-184, 2014. [PubMed: 24463507] [Full Text: https://doi.org/10.1038/nature12929]
Guo, H., Bettella, E., Marcogliese, P. C., Zhao, R., Andrews, J. C., Nowakowski, T. J., Gillentine, M. A., Hoekzema, K., Wang, T., Wu, H., Jangam, S., Liu, C., and 55 others. Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders. Nature Commun. 10: 4679, 2019. Note: Electronic Article. [PubMed: 31616000] [Full Text: https://doi.org/10.1038/s41467-019-12435-8]
Han, S., Nam, J., Li, Y., Kim, S., Cho, S.-H., Sho, Y. S., Choi, S.-Y., Choi, J., Han, K., Kim, Y., Na, M., Kim, H., Bae, Y. C., Choi, S.-Y., Kim, E. Regulation of dendritic spines, spatial memory, and embryonic development by the TANC family of PSD-95-interacting proteins. J. Neurosci. 30: 15102-15112, 2010. [PubMed: 21068316] [Full Text: https://doi.org/10.1523/JNEUROSCI.3128-10.2010]
Hartz, P. A. Personal Communication. Baltimore, Md. 1/29/2013.
Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 273-281, 2000. [PubMed: 10997877] [Full Text: https://doi.org/10.1093/dnares/7.4.271]
Stucchi, R., Plucinska, G., Hummel, J. J. A., Zahavi, E. E., Guerra San Juan, I., Klykov, O., Scheltema, R. A., Maarten Altelaar, A. F., Hoogenraad, C. C. Regulation of KIF1A-driven dense core vesicle transport: Ca(2+)/CaM controls DCV binding and liprin-alpha/TANC2 recruits DCVs to postsynaptic sites. Cell Rep. 24: 685-700, 2018. [PubMed: 30021165] [Full Text: https://doi.org/10.1016/j.celrep.2018.06.071]