Alternative titles; symbols
HGNC Approved Gene Symbol: TCTN2
Cytogenetic location: 12q24.31 Genomic coordinates (GRCh38) : 12:123,671,113-123,708,399 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.31 | ?Meckel syndrome 8 | 613885 | Autosomal recessive | 3 |
| Joubert syndrome 24 | 616654 | Autosomal recessive | 3 |
By searching databases for sequences similar to TCTN1 (609863), Reiter and Skarnes (2006) identified mouse and human TCTN2 and TCTN3 (613847). The deduced mouse Tctn2 protein contains 700 amino acids. It has an N-terminal signal peptide and a C-terminal transmembrane domain that is conserved in Drosophila tectonic.
Hartz (2011) mapped the TCTN2 gene to chromosome 12q24.31 based on an alignment of the TCTN2 sequence (GenBank AK023037) with the genomic sequence (GRCh37).
Shaheen et al. (2011) performed RT-PCR to quantitate expression of Tctn2 in various mouse adult tissues. Tctn2 expression was identified in all tissues, with significant expression in brain, kidney, and eye, organs affected by the MKS phenotype. Studies of developmental expression in the mouse detected significant expression at embryonic day 8.5 in the neural tube, most notably in the rhombomere of the future hindbrain. By embryonic day 10.5, Tctn2 mRNA was found throughout the mouse brain, the length of the neural tube, and the growing edge of the limb buds, heart, and eye. Furthermore, strong Tctn2 expression was observed in kidney from embryonic day 14.5 mouse embryo.
Meckel Syndrome 8
Shaheen et al. (2011) identified homozygosity for a splice site mutation in the TCTN2 gene (613846.0001) in a family segregating Meckel-Gruber syndrome-8 (MKS8; 613885).
Joubert Syndrome 24
In 6 patients from 3 unrelated families with Joubert syndrome-24 (JBTS24; 616654), Sang et al. (2011) identified 3 different homozygous mutations in the TCTN2 gene (613846.0002-613836.0004). The mutations were found by genome linkage analysis of families with ciliopathies and by targeting candidate genes identified through modeling of network disease pathways focused on ciliopathies. Functional studies of the variants were not performed, although all were predicted to result in a loss of function.
In a 7.5-year-old Turkish boy, born of consanguineous parents, with JBTS24, Huppke et al. (2015) identified a homozygous splice site mutation in the TCTN2 gene (613846.0002). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. No patient material was available for further studies.
Garcia-Gonzalo et al. (2011) found that Tctn2-null mouse embryos lacked nodal cilia, and that cilia in neural tubes were scarce and morphologically defective and failed to elongate axonemes. However, basal bodies docked normally to the plasma membrane. Cilia numbers were reduced in the limb bud mesenchyme, but cilia appeared normal. The findings were similar to those of Tctn1 (609863)-null mice, indicating a common function, and showed that Tctn1 and Tctn2 affect ciliogenesis in a tissue-specific manner. Garcia-Gonzalo et al. (2011) also demonstrated that Tctn2 and Tctn1 interact with other proteins in a large complex localized to the transition zone between the ciliary axoneme and the basal body.
In affected members of a multiplex consanguineous Arab family with Meckel-Gruber syndrome (MKS8; 613885), Shaheen et al. (2011) identified homozygosity for a splice site mutation in the TCTN2 gene at the -2 position of exon 14 (1506-2A-G) that disrupted splicing and created 2 aberrant transcripts. The first transcript introduces 104 basepairs from intron 13-14 and would delete 196 original amino acids, introduce 2 novel amino acids, and prematurely terminate the 697-amino acid protein at residue 504. The second transcript lacks exon 14 and would delete 195 original amino acids, introduce 4 novel amino acids, and prematurely terminate the protein at residue 507. The mutation segregated with the disease in the family and was not observed in 192 ethnically matched controls.
In a 7.5-year-old Turkish boy, born of consanguineous parents, with Joubert syndrome-24 (JBTS24; 616654), Huppke et al. (2015) identified a homozygous G-to-A transition (c.1235-1G-A, NM_024809.4) in intron 10 of the TCTN2 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in public databases, including dbSNP (build 138) or an in-house control database. The unaffected mother was heterozygous for the mutation. The mutation was predicted to result in the in-frame skipping of exon 11 and the loss of 26 amino acids. No cDNA was available from the patient to validate the consequences of the mutation on the transcript.
Sang et al. (2011) had previously identified this mutation (IVS10-1GA) in the TCTN2 gene in a 6-year-old Turkish girl (family A1443), born of consanguineous parents, with JBTS24. The mutation was demonstrated to result in the in-frame skipping of exon 11 in patient cells. The child's unaffected parents were heterozygous for the mutation, which was not found in control sets of 90 Caucasians and 86 ethnically matched individuals. The mutation was found by genome linkage analysis of families with ciliopathies and by targeting candidate genes identified through modeled network disease pathways focused on ciliopathies.
In 4 sibs (family MR20), born of consanguineous Pakistani parents, with Joubert syndrome-24 (JBTS24; 616654), Sang et al. (2011) identified a homozygous c.1873C-T transition in exon 16 of the TCTN2 gene, resulting in a gln625-to-ter (Q625X) substitution. The mutation segregated with the disorder in the family.
In a patient (UW95-3) of East Indian descent with Joubert syndrome-24 (JBTS24; 616654), Sang et al. (2011) identified a homozygous 1-bp insertion (c.77insG) in exon 1 of the TCTN2 gene, resulting in a frameshift and premature termination (Asp26GlyfsTer51).
Garcia-Gonzalo, F. R., Corbit, K. C., Sirerol-Piquer, M. S., Ramaswami, G., Otto, E. A., Noriega, T. R., Seol, A. D., Robinson, J. F., Bennett, C. L., Josifova, D. J., Garcia-Verdugo, J. M., Katsanis, N., Hildebrandt, F., Reiter, J. F. A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nature Genet. 43: 776-784, 2011. [PubMed: 21725307] [Full Text: https://doi.org/10.1038/ng.891]
Hartz, P. A. Personal Communication. Baltimore, Md. 3/29/2011.
Huppke, P., Wegener, E., Bohrer-Rabel, H., Bolz, H. J., Zoll, B., Gartner, J., Bergmann, C. Tectonic gene mutations in patients with Joubert syndrome. Europ. J. Hum. Genet. 23: 616-620, 2015. [PubMed: 25118024] [Full Text: https://doi.org/10.1038/ejhg.2014.160]
Reiter, J. F., Skarnes, W. C. Tectonic, a novel regulator of the Hedgehog pathway required for both activation and inhibition. Genes Dev. 20: 22-27, 2006. [PubMed: 16357211] [Full Text: https://doi.org/10.1101/gad.1363606]
Sang, L., Miller, J. J., Corbit, K. C., Giles, R. H., Brauer, M. J., Otto, E. A., Baye, L. M., Wen, X., Scales, S. J., Kwong, M., Huntzicker, E. G., Stakianos, M. K., and 20 others. Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 145: 513-528, 2011. [PubMed: 21565611] [Full Text: https://doi.org/10.1016/j.cell.2011.04.019]
Shaheen, R., Faqeih, E., Seidahmed, M. Z., Sunker, A., Alali, F. E., AlQahtani, K., Alkuraya, F. S. A TCTN2 mutation defines a novel Meckel Gruber syndrome locus. Hum. Mutat. 32: 573-578, 2011. [PubMed: 21462283] [Full Text: https://doi.org/10.1002/humu.21507]