HGNC Approved Gene Symbol: KCTD17
Cytogenetic location: 22q12.3 Genomic coordinates (GRCh38) : 22:37,051,742-37,063,390 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q12.3 | Dystonia 26, myoclonic | 616398 | Autosomal dominant | 3 |
Trichoplein (TCHP; 612654) is a negative regulator of ciliogenesis that interacts with the distal end of mother centrioles. By activating Aurora kinase A (AURKA; 603072), TCHP inhibits growth of primary cilia. KCTD17 is a substrate adaptor that interacts with both TCHP and CUL3 (603136)-RING (e.g., RBX1; 603814) E3 ubiquitin ligases, permitting polyubiquitination and degradation of TCHP, inactivation of AURKA, and growth of cilia (Kasahara et al., 2014).
Using a 2-step global E3 ubiquitin ligase screen to identify factors that could cause loss of TCHP from immortalized human retinal pigment epithelial (RPE1) cells, Kasahara et al. (2014) isolated KCTD17. The deduced 297-amino acid protein has an N-terminal BTB domain and a C-terminal coiled-coil region.
Mencacci et al. (2015) found expression of the KCTD17 gene in all human brain regions, with highest expression in the putamen followed by the thalamus. Immunostaining of SH-SY5 neuroblastoma cells showed that KCTD17 is diffusely distributed in the cytosol and does not localize at the plasma membrane. KCTD17 also did not colocalize with markers in the endoplasmic reticulum (ER), Golgi apparatus, mitochondria, or lysosomes. Gene expression profiling analysis suggested that KCTD17 is part of a network of genes involved in postsynaptic dopaminergic transmission.
Using RPE1 cells, Kasahara et al. (2014) found that TCHP disappeared from mother centrioles during serum withdrawal-induced ciliogenesis. Proteasome inhibition reversed loss of TCHP and blocked ciliogenesis following serum withdrawal. Protein pull-down and coimmunoprecipitation analyses of RPE1 cells revealed that KCTD17 interacted with CUL3 and RBX1 in an E3 ubiquitin ligase complex. In vitro reconstitution assays showed that KCTD17-CUL3-RBX1 caused polyubiquitination of TCHP in the presence of UBCH5A (UBE2D1; 602961) and UBCH5B (UBE2D2; 602962). Knockdown of KCTD17 in RPE1 cells disrupted serum withdrawal-induced loss of TCHP, caused failure to inactivate AURKA, and blocked ciliogenesis. Kasahara et al. (2014) concluded that KCTD17 is a critical adaptor that directs ubiquitination and proteasome-mediated degradation of TCHP, which is essential for ciliogenesis.
Hartz (2015) mapped the KCTD17 gene to chromosome 22q12.3 based on an alignment of the KCTD17 sequence (GenBank AK022304) with the genomic sequence (GRCh38).
In affected members of a British family with myoclonic dystonia-26 (DYT26; 616398), Mencacci et al. (2015) identified a heterozygous missense mutation in exon 4 of the KCTD17 gene (R145H; 616386.0001). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Sequencing the KCTD17 gene in 87 additional probands with familial myoclonic dystonia identified the same R145H mutation in a German proband. No KCTD17 mutations were found by direct screening of exon 4 in 358 patients with sporadic myoclonic dystonia. Studies of patient fibroblasts showed reduced and delayed cytosolic calcium signaling in response to stimulation, reduced calcium stores in the ER, and reduced intracellular calcium stores compared to controls.
In affected members of a British family with myoclonic dystonia-26 (DYT26; 616398), Mencacci et al. (2015) identified a heterozygous c.434G-A transition (c.434G-A, NM_001282684.1) in exon 4 of the KCTD17 gene, resulting in an arg145-to-his (R145H) substitution at a highly conserved residue. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the dbSNP (build 129), 1000 Genomes Project, or Exome Variant Server databases, or in 200 in-house control exomes. Sequencing the KCTD17 gene in 87 additional probands with familial myoclonic dystonia identified the same R145H mutation in affected members of a German family. Haplotype analysis did not suggest a founder effect. In vitro cellular expression studies showed that the mutant protein had normal subcelluar localization. Studies of patient fibroblasts showed reduced and delayed cytosolic calcium signaling in response to stimulation, reduced calcium stores in the ER, and reduced intracellular calcium stores compared to controls.
Hartz, P. A. Personal Communication. Baltimore, Md. 5/22/2015.
Kasahara, K., Kawakami, Y., Kiyono, T., Yonemura, S., Kawamura, Y., Era, S., Matsuzaki, F., Goshima, N., Inagaki, M. Ubiquitin-proteasome system controls ciliogenesis at the initial step of axoneme extension. Nature Commun. 5: 5081, 2014. Note: Electronic Article. [PubMed: 25270598] [Full Text: https://doi.org/10.1038/ncomms6081]
Mencacci, N. E., Rubio-Agusti, I., Zdebik, A., Asmus, F., Ludtmann, M. H. R., Ryten, M., Plagnol, V., Hauser, A.-K., Bandres-Ciga, S., Bettencourt, C., Forabosco, P., Hughes, D., and 21 others. A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia. Am. J. Hum. Genet. 96: 938-847, 2015. [PubMed: 25983243] [Full Text: https://doi.org/10.1016/j.ajhg.2015.04.008]