Alternative titles; symbols
HGNC Approved Gene Symbol: KCTD13
Cytogenetic location: 16p11.2 Genomic coordinates (GRCh38) : 16:29,906,339-29,926,226 (from NCBI)
Using the yeast 2-hybrid method to screen a human hepatocyte cDNA library with the small subunit of DNA polymerase delta (POLD2; 600815) as bait, He et al. (2001) isolated a cDNA encoding potassium channel tetramerization domain containing-13 (KCTD13). KCTD13 encodes a predicted 329-amino acid protein of 36.4 kD molecular mass, and shows 62% amino acid identity with B12 (TNFAIP1; 191161), a TNF (191160) early-response gene. Northern blot analysis showed ubiquitous expression of a 1.8-kb KCTD13 transcript, with highest expression levels in liver and kidney.
Using FISH, He et al. (2001) mapped the KCTD13 gene to 16p11.2.
By immunofluorescence and confocal microscopy, He et al. (2001) demonstrated that KCTD13 is a nuclear protein that colocalizes with PCNA (176740) at replication foci. They showed that recombinant KCTD13 binds to POLD2 and to PCNA in vitro, and GST pull-down assays demonstrated that KCTD13 binds these 2 proteins simultaneously. KCTD13 stimulates the polymerase activity of POLD2 when PCNA is present. He et al. (2001) identified a putative PCNA-binding motif at the C terminus of KCTD13 (QTKV-EFP), and Far Western analysis confirmed that a peptide of this motif binds PCNA. Similar to that of TNFAIP1, KCTD13 expression is induced by TNF-alpha and by IL6 (147620).
Golzio et al. (2012) dissected a region of the 16p11.2 chromosome that encompasses 29 genes that confers susceptibility to neurocognitive defects when deleted or duplicated. Overexpression of each human transcript in zebrafish embryos identified KCTD13 as the sole message capable of inducing the microcephaly phenotype associated with the 16p11.2 duplication (614671), whereas suppression of the same locus yielded the macrocephalic phenotype associated with the deletion (611913), capturing the mirror phenotypes of humans. Analyses of zebrafish and mouse embryos suggested that microcephaly is caused by decreased proliferation of neuronal progenitors with concomitant increase in apoptosis in the developing brain, whereas macrocephaly arises by increased proliferation and no changes in apoptosis. A role for KCTD13 dosage changes is consistent with autism in both a family with a reduced 16p11.2 deletion (Crepel et al., 2011) and a subject reported by Golzio et al. (2012) with a complex 16p11.2 rearrangement involving de novo structural alteration of KCTD13. Golzio et al. (2012) concluded that their data suggested that KCTD13 is a major driver for the neurodevelopmental phenotypes associated with the 16p11.2 CNV, reinforced the idea that one or a small number of transcripts within a CNV can underpin clinical phenotypes, and offered an efficient route to identifying dosage-sensitive loci.
Escamilla et al. (2017) deleted the Kctd13 gene in mice and demonstrated reduced synaptic transmission. Reduced synaptic transmission correlated with increased levels of RhoA (165390), a KCTD13/CUL3 ubiquitin ligase substrate, and was reversed by RhoA inhibition, suggesting increased RhoA as an important mechanism. In contrast to the study of Golzio et al. (2012), deletion of Kctd13 or kctd13 did not increase brain size or neurogenesis in mice or zebrafish, respectively. These findings implicated Kctd13 in the regulation of neuronal function relevant to neuropsychiatric disorders and clarified the role of this gene in neurogenesis and brain size. Escamilla et al. (2017) concluded that their data also revealed a potential role for RhoA as a therapeutic target in disorders associated with KCTD13 deletion.
Arbogast et al. (2019) found that homozygous and heterozygous Kctd13-deficient mice had no prenatal lethality and had normal gross postnatal growth and viability compared with wildtype. However, both heterozygous and homozygous Kctd13-deficient mice showed deficits in short-term recognition memory associated with a spine maturation deficit in the CA1 region of hippocampus. Transcriptome analyses revealed dysregulation of Dctn5 (612962), Mapk3 (601795), and genes associated with neurodevelopmental disorders in Kctd13-deficient mice. Double-heterozygous Kctd13/Mvp (605088) and Kctd13/Lat (602354) mice displayed sex-specific brain structure alterations, recapitulating previously observed genetic interactions during zebrafish development.
Arbogast, T., Razaz, P., Ellegood, J., McKinstry, S. U., Erdin, S., Currall, B., Aneichyk, T., Lerch, J. P., Qiu, L. R., Rodriguiz, R. M., Henkelman, R. M., Talkowski, M. E., Wetsel, W. C., Golzio, C., Katsanis, N. Kctd13-deficient mice display short-term memory impairment and sex-dependent genetic interactions. Hum. Molec. Genet. 28: 1474-1486, 2019. [PubMed: 30590535] [Full Text: https://doi.org/10.1093/hmg/ddy436]
Crepel, A., Steyaert, J., De la Marche, W., De Wolf, V., Fryns, J.-P., Noens, I., Devriendt, K., Peeters, H. Narrowing the critical deletion region for autism spectrum disorders on 16p11.2. (Letter) Am. J. Med. Genet. 156B: 243-245, 2011. [PubMed: 21302354] [Full Text: https://doi.org/10.1002/ajmg.b.31163]
Escamilla, C. O., Filonova, I., Walker, A. K., Xuan, Z. X., Holehonnur, R., Espinosa, F., Liu, S., Thyme, S. B., Lopez-Garcia, I. A., Mendoza, D. B., Usui, N., Ellegood, J., Eisch, A. J., Konopka, G., Lerch, J. P., Schier, A. F., Speed, H. E., Powell, C. M. Kctd13 deletion reduces synaptic transmission via increased RhoA. Nature 551: 227-231, 2017. [PubMed: 29088697] [Full Text: https://doi.org/10.1038/nature24470]
Golzio, C., Willer, J., Talkowski, M. E., Oh, E. C., Taniguchi, Y., Jacquemont, S., Reymond, A., Sun, M., Sawa, A., Gusella, J. F., Kamiya, A., Beckmann, J. S., Katsanis, N. KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature 485: 363-367, 2012. [PubMed: 22596160] [Full Text: https://doi.org/10.1038/nature11091]
He, H., Tan, C.-K., Downey, K. M., So, A. G. A tumor necrosis factor alpha- and interleukin 6-inducible protein that interacts with the small subunit of DNA polymerase delta and proliferating nuclear cell antigen. Proc. Nat. Acad. Sci. 98: 11979-11984, 2001. [PubMed: 11593007] [Full Text: https://doi.org/10.1073/pnas.221452098]