Alternative titles; symbols
HGNC Approved Gene Symbol: TTC21B
Cytogenetic location: 2q24.3 Genomic coordinates (GRCh38) : 2:165,873,362-165,953,776 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q24.3 | Nephronophthisis 12 | 613820 | Autosomal dominant; Autosomal recessive | 3 |
| Short-rib thoracic dysplasia 4 with or without polydactyly | 613819 | Autosomal recessive | 3 |
The TTC21B gene encodes an axonemal protein required for retrograde intraflagellar transport and involved in ciliary function (Tran et al., 2008).
Tran et al. (2008) isolated the TTC21B gene and determined that it encodes THM1, a 'tetratricopeptide repeat-containing hedgehog modulator-1,' which localizes to cilia. The deduced 1,317-amino acid protein has a molecular mass of approximately 150 kD and is predicted to contain 11 tetratricopeptide repeat (TPR) domains. Tran et al. (2008) found that the Ttc21b gene is responsible for the 'alien' (aln) locus in mouse (see ANIMAL MODEL). In normal embryonic mice at day 10.5, Ttc21b and Ttc21a (611430) were widely expressed, with more intense expression in the maxillary prominence, branchial arches, limb buds, somites, and spinal cord. Ttc21a encodes a protein that is 49% identical to THM1 and has a similar predicted protein structure.
The TTC21B gene contains 29 exons (Davis et al., 2011).
Given the role of Ttc21b in mutant 'alien' mice, which show ciliary defects, Davis et al. (2011) examined the role of TTC21B in human ciliopathies. Among a clinically diverse cohort of 753 patients with some form of ciliopathy, they found that affected members of 4 families with nephronophthisis (NPHP12; 613820) and 1 patient from 1 family with a more severe phenotype consistent with Jeune asphyxiating thoracic dystrophy (SRTD4; 613819) were homozygous or compound heterozygous for mutations in the TTC21B gene (612014.0001-612014.0003 and 612014.0004-612014.0005, respectively). No clinical details were given on the patients, except that some with NPHP12 had early onset and an extrarenal phenotype. All of these mutations were demonstrated to be either null or hypomorphic alleles by in vivo and in vitro complementation studies in mutant zebrafish, mammalian cells, and rodent photoreceptor sensory cilia. In addition, heterozygous functionally pathogenic alleles were found in about 5% of the total cohort, including 3 unrelated patients with Joubert syndrome-11 (JBTS11), suggesting that TTC21B might be a common contributor to the total mutational load in ciliopathies. About one-third of the cases with heterozygous TTC21B alleles also had mutant trans alleles in 13 different known ciliopathy genes (see, e.g., BBS1, 209901). The report demonstrated that genetic lesions can be both causally associated with diverse ciliopathies and interact in trans with other disease-causing genes, resulting in a broad range of phenotypes and a complex pattern of inheritance involving variation across multiple sites of the ciliary proteome.
In a British adult and an 8-year-old Chinese child diagnosed with Jeune ATD, McInerney-Leo et al. (2015) performed whole-exome sequencing and identified biallelic mutations in the TTC21B gene (612014.0006-612014.0008).
Tran et al. (2008) found that the Ttc21b gene is responsible for the 'alien' (aln) locus in mouse. Aln mutant cilia have bulb-like structures at their tips in which intraflagellar transport (IFT) proteins such as Ift88 (600595) are sequestered, characteristic of Chlamydomonas reinhardtii and Caenorhabditis elegans retrograde IFT mutants. RNA interference knockdown of Ttc21b in mouse intermedullary collecting duct cells expressing an Ift88-enhanced yellow fluorescent protein fusion recapitulated the aln-mutant cilial phenotype, and live imaging of these cells revealed impaired retrograde intraflagellar transport. In contrast to previously described IFT mutants, Smoothened (601500) and full-length glioblastoma (GLI; 165220) proteins localize to aln-mutant cilia. Tran et al. (2008) hypothesized that the aln retrograde IFT defect causes sequestration of IFT proteins in aln-mutant cilia and leads to the overactivated Sonic hedgehog (SHH; 600725) signaling phenotype. Specifically, the aln mutation uncouples the roles of anterograde and retrograde transport in Sonic hedgehog signaling, suggesting that anterograde IFT is required for GLI activation and that retrograde IFT modulates this event.
In affected members of 2 unrelated consanguineous families with nephronophthisis-12 (NPHP12; 613820), Davis et al. (2011) identified a homozygous mutation in exon 6 of the TTC21B gene, resulting in a pro209-to-leu (P209L) substitution in a TPR domain. One family was of Portuguese and the other of Egyptian descent. The mutation was not found in 796 controls. In vitro and in vivo functional expression studies in mammalian cells and zebrafish indicated that the mutant protein was a hypomorphic allele. In 2 additional families with early-onset NPHP with extrarenal manifestations, the P209L allele was found in compound heterozygosity with another pathogenic TTC21B allele: a cys552-to-ter (C552X; 612014.0002) substitution in exon 13 and an A-to-G transition in intron 20 (612014.0003), respectively. Both of the latter mutations were shown by expression studies to be functionally null alleles. Haplotype analysis indicated a founder effect for the P209L allele.
For discussion of the cys552-to-ter (C552X) mutation in the TTC21B gene that was found in compound heterozygous state in patients with nephronophthisis-12 (NPHP12; 613820) by Davis et al. (2011), see 612014.0001.
For discussion of the A-G transition in intron 20 of the TTC21B gene that was found in compound heterozygous state in patients with nephronophthisis-12 (NPHP12; 613820) by Davis et al. (2011), see 612014.0001.
In a patient of northern European origin with a phenotype consistent with asphyxiating thoracic dystrophy (SRTD4; 613819), Davis et al. (2011) identified compound heterozygosity for 2 mutations in the TTC21B gene: an arg411-to-ter (R411X) substitution in exon 10 and a leu795-to-pro (L795P; 612014.0005) substitution in a TPR domain in exon 18. Neither mutation was seen in 796 controls. In vitro and in vivo functional expression studies in mammalian cells and zebrafish indicated that the L795P mutant protein was a hypomorphic allele.
For discussion of the leu795-to-pro (L795P) mutation in the TTC21B gene that was found in compound heterozygous state in a patient with a phenotype consistent with asphyxiating thoracic dystrophy (SRTD4; 613819) by Davis et al. (2011), see 612014.0004.
In a British adult (SKPD-203.3) with short-rib thoracic dysplasia without polydactyly (SRTD4; 613819), McInerney-Leo et al. (2015) identified compound heterozygosity for mutations in the TTC21B gene: a splice site mutation in intron 3 (c.152-2A-G, NM_024753), and a c.3605T-C transition in exon 26, resulting in a leu1202-to-pro (L1202P; 612014.0005) substitution. Neither mutation was found in internal or public variant databases.
For discussion of the c.3605T-C transition (c.3605T-C, NM_024753) in exon 26 of the TTC21B gene, resulting in a leu1202-to-pro (L1202P) substitution, that was found in compound heterozygous state in a British adult patient (SKPD-203.3) with short-rib thoracic dysplasia without polydactyly (SRTD4; 613819) by McInerney-Leo et al. (2015), see 612014.0006.
In an 8-year-old Chinese patient (SKPD-208.3) with short-rib thoracic dysplasia with polydactyly (SRTD4; 613819), McInerney-Leo et al. (2015) identified homozygosity for a 4-bp insertion (c.268_269insTAGA, NM_024753) in exon 4 of the TTC21B gene, causing a frameshift predicted to result in a premature termination codon (Glu90_Ala91insTer). The mutation was not found in internal or public variant databases. Two additional mutations in SRTD-associated genes were detected in heterozygosity in this patient, an R560L substitution in the DYNC2H1 gene (603297) and an L328F substitution in the EVC gene (604831); the authors noted that it was possible that these variants might modify the SRTD phenotype.
Davis, E. E., Zhang, Q., Liu, Q., Diplas, B. H., Davey, L. M., Hartley, J., Stoetzel, C., Szymanska, K., Ramaswami, G., Logan, C. V., Muzny, D. M., Young, A. C., and 36 others. TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nature Genet. 43: 189-196, 2011. Note: Erratum: Nature Genet. 43: 499 only, 2011. [PubMed: 21258341] [Full Text: https://doi.org/10.1038/ng.756]
McInerney-Leo, A. M., Harris, J. E., Leo, P. J., Marshall, M. S., Gardiner, B., Kinning, E., Leong, H. Y., McKenzie, F., Ong, W. P., Vodopiutz, J., Wicking, C., Brown, M. A., Zankl, A., Duncan, E. L. Whole exome sequencing is an efficient, sensitive and specific method for determining the genetic cause of short-rib thoracic dystrophies. Clin. Genet. 88: 550-557, 2015. [PubMed: 25492405] [Full Text: https://doi.org/10.1111/cge.12550]
Tran, P. V., Haycraft, C. J., Besschetnova, T. Y., Turbe-Doan, A., Stottmann, R. W., Herron, B. J., Chesebro, A. L., Qiu, H., Scherz, P. J., Shah, J. V., Yoder, B. K., Beier, D. R. THM1 negatively modulates mouse Sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. Nature Genet. 40: 403-410, 2008. [PubMed: 18327258] [Full Text: https://doi.org/10.1038/ng.105]