Alternative titles; symbols
HGNC Approved Gene Symbol: TCTN3
SNOMEDCT: 239031000;
Cytogenetic location: 10q24.1 Genomic coordinates (GRCh38) : 10:95,663,401-95,693,927 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q24.1 | Joubert syndrome 18 | 614815 | Autosomal recessive | 3 |
| Orofaciodigital syndrome IV | 258860 | Autosomal recessive | 3 |
By searching databases for sequences similar to TCTN1 (609863), Reiter and Skarnes (2006) identified mouse and human TCTN2 (613846) and TCTN3. The deduced mouse Tctn3 protein contains 595 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 TCTN3 gene to chromosome 10q24.1 based on an alignment of the TCTN3 sequence (GenBank AL050022) with the genomic sequence (GRCh37).
Orofaciodigital Syndrome IV
In 6 fetuses from 5 consanguineous families with orofaciodigital syndrome IV (OFD4; 258860), Thomas et al. (2012) identified homozygosity or compound heterozygosity for truncating mutations in the TCTN3 gene (613847.0001-613847.0005). Functional analysis indicated that TCTN3 is necessary for transduction of the SHH (600725) signaling pathway, as revealed by abnormal processing of GLI3 (165240) in patient cells.
Joubert Syndrome 18
By analysis of TCTN3 in a Turkish family with Joubert syndrome mapping to chromosome 10 (JBTS18; 614815), Thomas et al. (2012) identified homozygosity for a missense mutation (613847.0006) in the 2 affected sibs.
In a 12-year-old boy (patient 1), born of first-cousin Persian parents, with JBTS18, Huppke et al. (2015) identified homozygosity for a splice site mutation in the TCTN3 gene (613847.0007).
In a fetus with orofaciodigital syndrome IV (OFD4; 258860) from a consanguineous Senegalese family, Thomas et al. (2012) identified homozygosity for a 1222C-T transition in exon 11 of the TCTN3 gene, resulting in a gln408-to-ter (Q408X) substitution. Patient fibroblasts displayed negligible responsiveness to SHH (600725) agonists compared to controls, and mutant fibroblasts exhibited decreased amounts of full-length unprocessed GLI3 (165240), a transcriptional target of SHH signaling, and increased amounts of the cleaved repressor form (GLI3R), indicating that TCTN3 is essential for GLI3 processing and function. Thomas et al. (2012) concluded that at least some of the defects in affected individuals with TCTN3 mutations may be secondary to reduced SHH signaling.
In 2 fetuses with orofaciodigital syndrome IV (OFD4; 258860) from 2 unrelated consanguineous Pakistani families, Thomas et al. (2012) identified homozygosity for a 4-bp deletion (650_653del) in exon 5 of the TCTN3 gene, predicted to cause a frameshift resulting in premature termination (Tyr217SerfsTer6). The mutation segregated in all available family members from both families with the expected patterns of autosomal recessive inheritance.
In a fetus with orofaciodigital syndrome IV (OFD4; 258860) from a consanguineous Tunisian family, Thomas et al. (2012) identified homozygosity for a 1327C-T transition in exon 12 of the TCTN3 gene, resulting in a gln443-to-ter (Q443X) substitution. The mutation segregated in all available family members with the expected patterns of autosomal recessive inheritance.
In 2 fetal sibs with orofaciodigital syndrome IV (OFD4; 258860) from a consanguineous French family, Thomas et al. (2012) identified compound heterozygosity for two 2-bp deletions in the TCTN3 gene: one in exon 4 (566_567del) resulting in a frameshift and premature termination (Glu189ValfsTer52), and the other in exon 12 (1348_1349del; 613847.0005) resulting in a frameshift and premature termination (Leu450SerfsTer14).
For discussion of the 2-bp deletion in the TCTN3 gene (1348_1349del) that was found in compound heterozygous state in 2 fetal sibs with orofaciodigital syndrome IV (OFD4; 258860) by Thomas et al. (2012), see 613847.0004.
In 2 sibs with Joubert syndrome (JBTS18; 614815) from a consanguineous Turkish family, Thomas et al. (2012) identified homozygosity for a 940G-A transition in exon 8 of the TCTN3 gene, resulting in a gly314-to-arg (G314R) substitution at a highly conserved residue. The mutation was not found in the SNP or 1000 Genomes Project databases or in 150 ethnically matched chromosomes.
In a 12-year-old boy (patient 1), born of first-cousin Persian parents, with Joubert syndrome-18 (JBTS18; 614815), Huppke et al. (2015) identified homozygosity for a c.853-1G-T transversion (c.853-1G-T, NM_015631.5) in the TCTN3 gene, resulting in the skipping of exon 7 and an in-frame deletion of 10 amino acids. The mutation, which was found by next-generation sequencing of a targeted ciliopathy multigene panel and confirmed by Sanger sequencing, segregated with the phenotype. The variant was not present in public databases.
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]
Thomas, S., Legendre, M., Saunier, S., Bessieres, B., Alby, C., Bonniere, M., Toutain, A., Loeuillet, L., Szymanska, K., Jossic, F., Gaillard, D., Yacoubi, M. T., and 14 others. TCTN3 mutations cause Mohr-Majewski syndrome. Am. J. Hum. Genet. 91: 372-378, 2012. [PubMed: 22883145] [Full Text: https://doi.org/10.1016/j.ajhg.2012.06.017]