HGNC Approved Gene Symbol: TTBK2
SNOMEDCT: 719207000;
Cytogenetic location: 15q15.2 Genomic coordinates (GRCh38): 15:42,738,730-42,921,000 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q15.2 | Spinocerebellar ataxia 11 | 604432 | Autosomal dominant | 3 |
Single nonmotile cilia, or primary cilia, are dynamic signaling organelles required for organ and limb patterning during embryonic development. Cilia arise from the basal body, a modified form of the mother centriole, and are disassembled during the cell cycle to enable centrioles to become components of the spindle poles during mitosis. TTBK2 is critical for regrowth of cilia following exit from the cell cycle (Goetz et al., 2012).
Houlden et al. (2007) characterized the TTBK2 gene. TTBK2 produces a 5.6-kb transcript in which the longest open reading frame is 3,732 nucleotides, encoding a protein of 1,244 amino acids. The gene is alternatively spliced, with ubiquitous expression in human adult and fetal tissues. The N terminus of TTBK2 has a serine-threonine-tyrosine kinase domain, and a C-terminal region shows homology to TTBK1. By in situ hybridization, Houlden et al. (2007) showed that TTBK2 was expressed in all brain regions in human, rat, and mouse tissue. There was particularly high expression in Purkinje cells of the cerebellum, granular cell layer, hippocampus, midbrain, and substantia nigra. Lower expression was seen in the cortex of human, rat, and mouse brains.
By expressing fluorescence-tagged proteins in ciliated cells, Goetz et al. (2012) found that mouse and human TTBK2 localized to the ciliary transition zone, between the axoneme and the basal body. During mitosis, TTBK2 showed a diffuse cytoplasmic distribution. It did not localize to spindle poles of dividing cells.
Houlden et al. (2007) determined that the TTBK2 gene comprises 16 exons.
Houlden et al. (2007) localized the TTBK2 to chromosome 15q15.2, within a critical region linked to spinocerebellar ataxia (SCA11; 604432).
Goetz et al. (2012) stated that the mouse Ttbk2 gene maps to chromosome 2.
TTBK2 encodes a member of the casein kinase (CK1) group of eukaryotic protein kinases, as indicated by its ability to phosphorylate tau (157140) and tubulin (see 602529) in vitro. TTBK1 (619415) has been implicated in Alzheimer disease (104300) and in tangle formation (Sato et al., 2006). The 2 TTBK2 phosphorylation sites in tau (ser208 and ser210) are priming sites for the phosphorylation of tau by GSK-3-beta (605004), which influences tau pathology.
Taylor et al. (2018) showed that patients with frontotemporal lobar degeneration (FTLD) with tau inclusions (see 600274) or TDP43 (TARDBP; 605078) inclusions (see 607485) had elevated expression of both TTBK1 and TTBK2 in cortical and hippocampal neurons and that TTBK1 and TTBK2 colocalized with phosphorylated proteins.
Spinocerebellar ataxia-11 (SCA11; 604432) is a pure progressive cerebellar ataxia that has been linked to 15q14-q21 (Worth et al., 1999). Houlden et al. (2007) narrowed the assignment to a 5.6-cM region containing 134 genes. In affected members of an 8-generation English family with SCA11, Houlden et al. (2007) identified a 1-base insertion in the TTBK2 gene creating a premature stop codon and a truncation of the normal protein (611695.0001). In affected members of a second family, of Pakistani ancestry, they identified a different TTBK2 mutation (611695.0002).
Goetz et al. (2012) identified an N-ethyl-N-nitrosourea-induced mouse mutation, bartleby (bby), based on the similarity of defects in homozygous mutant embryos with those seen in mutants lacking cilia. Defects included holoprosencephaly, twisted body axis, abnormal limb development, and randomized laterality of heart looping. Bby/bby embryos died at midgestation. Molecular analysis of bby/bby neural tube revealed widespread disruption of cilia-dependent Shh (600725) signaling in the neural tube and limb. Scanning electron microscopy of bby/bby neural tube revealed normal organization of centrioles and normal maturation and membrane docking of basal bodies, but no cilia extending from the basal bodies. Goetz et al. (2012) identified the bby mutation as an A-to-T transversion in the Ttbk2 gene that converted lys142 to a stop codon (K142X), truncating the protein within the kinase domain. By comparing axoneme assembly in wildtype and bby/bby embryonic fibroblasts, Goetz et al. (2012) found that Ttbk2 was required to remove basal body capping protein Cp110 (CCP110; 609544) from the distal end of the mother centriole, permitting initiation of ciliogenesis. A kinase-dead form of Ttbk2 localized correctly to the mother centriole, but it failed to rescue cilia formation of bby mutant cells. C-terminally truncated forms of human TTBK2, similar to mutations associated with SCA11, inefficiently localized to the mother centriole and failed to rescue ciliogenesis in bby mutant cells. Goetz et al. (2012) concluded that TTBK2 is required for removal of CP110 for the initiation of ciliogenesis.
Taylor et al. (2018) showed that transgenic C. elegans expressing the kinase catalytic domain of human TTBK1 or TTBK2 were behaviorally normal. However, C. elegans coexpressing TTBK1 or TTBK2 with tau caused neurodegeneration, behavioral abnormalities, aberrant phosphorylation, and shortened lifespan. Coexpression of TTBK2 with high levels of tau resulted in lethality. Coexpression of TTBK1, but not TTBK2, with TDP43 (605078) led to behavioral abnormalities and increased phosphorylation of TDP43. The authors concluded that TTBK1 and TTBK2 are kinases for both tau and TDP43.
In affected members of an English family from Devon with spinocerebellar ataxia-11 (SCA11; 604432) in 8 generations, Houlden et al. (2007) identified a 1-base insertion of an adenosine at nucleotide 1329 in exon 13 of the TTBK2 gene (1329insA). This created a premature stop site (TGA) in the mRNA at codon 450, truncating the normal protein from 1,244 to 450 amino acids.
In a family of Pakistani ancestry with 5 individuals over 3 generations presenting with spinocerebellar ataxia (SCA11; 604432), Houlden et al. (2007) identified a frameshift deletion of 2 bases (GA) in exon 13 of TTBK2 at nucleotides 1284 and 1285 in codons 428 and 429 (1284_1285delAG). The deletion created a premature stop site (TGA) in mRNA at codon 449.
Goetz, S. C., Liem, K. F., Jr., Anderson, K. V. The spinocerebellar ataxia-associated gene Tau tubulin kinase 2 controls the initiation of ciliogenesis. Cell 151: 847-858, 2012. [PubMed: 23141541] [Full Text: https://doi.org/10.1016/j.cell.2012.10.010]
Houlden, H., Johnson, J., Gardner-Thorpe, C., Lashley, T., Hernandez, D., Worth, P., Singleton, A. B., Hilton, D. A., Holton, J., Revesz, T., Davis, M. B., Giunti, P., Wood, N. W. Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11. Nature Genet. 39: 1434-1436, 2007. Note: Erratum: Nature Genet. 40: 255 only, 2008. [PubMed: 18037885] [Full Text: https://doi.org/10.1038/ng.2007.43]
Sato, S., Cerny, R. L., Buescher, J. L., Ikezu, T. Tau-tubulin kinase 1 (TTBK1), a neuron-specific tau kinase candidate, is involved in tau phosphorylation and aggregation. J. Neurochem. 98: 1573-1584, 2006. [PubMed: 16923168] [Full Text: https://doi.org/10.1111/j.1471-4159.2006.04059.x]
Taylor, L. M., McMillan, P. J., Liachko, N. F., Strovas, T. J., Ghetti, B., Bird, T. D., Keene, C. D., Kraemer, B. C. Pathological phosphorylation of tau and TDP-43 by TTBK1 and TTBK2 drives neurodegeneration. Molec. Neurodegener. 13: 7, 2018. [PubMed: 29409526] [Full Text: https://doi.org/10.1186/s13024-018-0237-9]
Worth, P. F., Giunti, P., Gardner-Thorpe, C., Dixon, P. H., Davis, M. B., Wood, N. W. Autosomal dominant cerebellar ataxia type III: linkage in a large British family to a 7.6-cM region on chromosome 15q14-21.3. Am. J. Hum. Genet. 65: 420-426, 1999. [PubMed: 10417284] [Full Text: https://doi.org/10.1086/302495]