Alternative titles; symbols
HGNC Approved Gene Symbol: TCTN1
Cytogenetic location: 12q24.11 Genomic coordinates (GRCh38) : 12:110,614,129-110,649,430 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.11 | Joubert syndrome 13 | 614173 | Autosomal recessive | 3 |
Reiter and Skarnes (2006) identified mouse and human TCTN1, which they named tectonic, after the Greek work for builder, due to its apparent involvement in a diverse range of developmental processes. The deduced mouse protein contains 593 amino acids and has an N-terminal signal peptide. Database analysis indicated that tectonic is the founding member of a family of evolutionarily conserved secreted and transmembrane proteins that includes mouse and human TCTN2 (613846) and TCTN3 (613847) and the single Drosophila tectonic homolog. In mouse embryos, tectonic was expressed in regions that participate in hedgehog (see SHH; 600725) signaling. It was first expressed during gastrulation stages in the ventral node. At embryonic day 9.5, it was expressed in the gut endoderm, limb buds, notochord, somites, neural tube, and floorplate.
Reiter and Skarnes (2006) determined that the mouse tectonic gene contains 13 exons.
Gross (2011) mapped the TCTN1 gene to chromosome 12q24.11 based on an alignment of the TCTN1 sequence (GenBank BC040113) with the genomic sequence (GRCh37).
Reiter and Skarnes (2006) mapped the mouse tectonic gene to chromosome 5.
Reiter and Skarnes (2006) found that mouse tectonic modulated hedgehog (see SHH; 600725) signaling downstream of smoothened (SMOH; 601500) and Rab23 (606144) and was required for maximal hedgehog activation.
Using mass spectrometric analysis and immunoprecipitation studies of mouse proteins and cultured murine cells, Garcia-Gonzalo et al. (2011) showed that Tctn1 is part of a ciliopathy-associated protein complex and interacts with several genes associated with ciliopathies, including Mks1 (609883), Cc2d2a (612013), and Tctn2 (613846). The 2 strongest interactors were Tctn2 and Tctn3 (613847), indicating that these 3 tectonic proteins are part of the same complex. TCTN1 also interacted with B9d1 (614144) and Tmem216 (613277), Tmem67 (609884), and Cep290 (610142) under some conditions. In cultured ciliated cells, Tctn1 localized with these proteins to the transition zone between the ciliary axoneme and the basal body, where it regulates ciliogenesis in a tissue-dependent manner. Studies of fibroblasts derived from Tctn1-null mice showed that the tectonic complex also controls ciliary membrane composition, and is needed for proper ciliary localization of Adcy3 (600291), Pkd2 (173910), Smo (601500), and Arl13b (608922).
By homozygosity mapping followed by candidate gene sequencing, Garcia-Gonzalo et al. (2011) identified a homozygous splice site mutation in the TCTN1 gene (609863.0001) in 2 sisters, born of consanguineous Bangladeshi parents, with Joubert syndrome-13 (JBTS13; 614173). Investigation of 4 families homozygous at the TCTN1 locus and 48 families with JBTS identified no additional mutations, suggesting that TCTN1 mutations are a rare cause of Joubert syndrome.
In a 27-week-old male fetus with JBTS13, Srour et al. (2015) identified compound heterozygous mutations in the TCTN1 gene (609863.0001 and 609863.0002). The mutations were found by whole-exome sequencing. Functional studies and studies of patient cells were not performed.
Reiter and Skarnes (2006) found that tectonic-null mice died between embryonic days 13.5 and 16.5 and displayed holoprosencephaly. V3 interneurons were lost in tectonic mutants. Loss of ventral neural markers in tectonic-null mice was accompanied by a ventral expansion of genes normally restricted to more dorsal domains. Examination of tectonic-Shh double mutants showed that tectonic could repress as well as activate hedgehog signaling.
By studies in Tctn1-null mice, Garcia-Gonzalo et al. (2011) determined that Tctn1 is required for ciliogenesis in a tissue-dependent manner. Tctn1-null mice showed disruption of nodal flow, laterality defects, and neural tube dorsalization. Basal bodies docked to the cellular plasma membrane, but failed to extend axonemes. However, cilia were present in the notochord, early gut epithelium, and mesenchymal cells surrounding the neural tube and in the limb bud. Tctn1 -/- embryos developed an extra preaxial digit on 1 or both hindlimbs. Although Shh expression was normal, downstream signaling was disturbed, suggesting that Tctn1 is required for cilium-dependent Shh signal transduction. Tctn2 (613846)-null and Cc2d2a (612013)-null mice showed a similar phenotype, suggesting that these 3 genes share a common function affecting ciliogenesis in a tissue-specific manner.
By homozygosity mapping followed by candidate gene sequencing in 2 sisters, born of consanguineous Bangladeshi parents, with Joubert syndrome-13 (JBTS13; 614173), Garcia-Gonzalo et al. (2011) identified a homozygous A-to-G transition in intron 1 of the TCTN1 gene, resulting in a splice site mutation predicted to disrupt domains of the protein required for its function. The mutation was not found in 96 controls or in the 1000 Genomes Project data. Brain MRI showed cerebellar vermis hypoplasia and the molar tooth sign, the characteristic radiographic feature of JBTS. One girl also had bilateral frontotemporal pachygyria. Ophthalmologic assessment and renal ultrasounds were normal at ages 7 years and 4 years, respectively.
In a 27-week-old male fetus (HSJ-JBTS-2) with JBTS13, Srour et al. (2015) identified compound heterozygous mutations in the TCTN1 gene: c.342-2A-C (c.342-2A-C, NM_001082538.2), which the authors stated was the same as the mutation identified by Garcia-Gonzalo et al. (2011), and a c.898C-T transition, resulting in an arg300-to-ter (R300X; 609863.0002) substitution. The mutations were found by whole-exome sequencing. Functional studies and studies of patient cells were not performed.
For discussion of the c.898C-T transition (c.898C-T, NM_001082538.2) in the TCTN1 gene, resulting in an arg300-to-ter (R300X) substitution, that was found in compound heterozygous state in a fetus with Joubert syndrome-13 (JBTS13; 614173) by Srour et al. (2015), see 609863.0001.
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]
Gross, M. B. Personal Communication. Baltimore, Md. 3/29/2011.
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]
Srour, M., Hamdan, F. F., McKnight, D., Davis, E., Mandel, H., Schwartzentruber, J., Martin, B., Patry, L., Nassif, C., Dionne-Laporte, A., Ospina, L. H., Lemyre, E., and 22 others. Joubert syndrome in French Canadians and identification of mutations in CEP104. Am. J. Hum. Genet. 97: 744-753, 2015. [PubMed: 26477546] [Full Text: https://doi.org/10.1016/j.ajhg.2015.09.009]