Alternative titles; symbols
HGNC Approved Gene Symbol: CDK13
Cytogenetic location: 7p14.1 Genomic coordinates (GRCh38): 7:39,950,256-40,099,580 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p14.1 | Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder | 617360 | Autosomal dominant | 3 |
CDK13 forms a complex with cyclin K (CCNK; 603544) and is predicted to have a role in gene regulation (Blazek et al., 2011).
Lapidot-Lifson et al. (1992) cloned a glioblastoma cDNA encoding a protein related to the S. pombe cdc2 kinase. They designated the predicted 418-amino acid protein CHED, for cholinesterase-related cell division controller. The CHED protein shares 34 to 42% sequence identity with human CDC2 (116940), S. cerevisiae Cdc28, and S. pombe Cdc2, 3 functionally interchangeable proteins. Northern blot analysis revealed that CHED is expressed as 2.2- to 2.3-kb mRNAs in several fetal tissues and tumor cell lines.
Using an antisense oligonucleotide, Lapidot-Lifson et al. (1992) found that reduced CHED expression selectively inhibited megakaryocyte development in murine bone marrow cultures but did not prevent other hematopoietic pathways. Antisense mRNA inhibition of BCHE (177400) expression had a similar effect. The authors suggested that CHED and BCHE are interrelated components responsive to cholinergic signals in the hematopoietic pathway. They stated that a link between cholinergic signaling and cell division might be mediated through individual CDC proteins in a cell lineage-specific manner.
Using mass spectrometric techniques and reciprocal immunoprecipitation analysis with HEK293 cells, Blazek et al. (2011) found that CYCK interacted with CDK12 (615514) and CDK13 in separate protein complexes. Microarray and RT-PCR analyses showed that knockdown of CYCK or CDK12, but not CDK13, altered expression of long complex genes and induced DNA damage and cell-cycle checkpoint. Blazek et al. (2011) concluded that the CYCK-CDK12 and CYCK-CDK13 complexes have unique functions in gene regulation.
Using database analysis and experimental approaches, Insco et al. (2023) showed that CDK13 had properties consistent with a tumor suppressor. CDK13 mutations in melanoma (see 155600), especially those in the kinase domain, abrogated its kinase activity and produced dominant-negative activity over wildtype CDK13. CDK13 mutations associated with melanoma caused accumulation of prematurely terminated RNAs (ptRNAs) generated from existing cleavage and polyadenylation sites found in intronic DNA. ptRNAs accumulated posttranscriptionally due to loss of degradation by the nuclear exosome in CDK13 mutant cells. Rather than being degraded, ptRNAs were exported to the cytoplasm, where they, including their intronic sequences, were translated into truncated proteins. Mutant CDK13 expression caused inefficient recruitment of the PAXT complex, which degrades ptRNAs, leading to disruption of the polyA RNA exosome and stabilization of ptRNAs. Database analysis and studies with a zebrafish model confirmed that ptRNA accumulation is oncogenic.
Gross (2012) mapped the CDK13 gene to chromosome 7p14.1 based on an alignment of the CDK13 sequence (GenBank AJ297709) with the genomic sequence (GRCh37).
In 7 unrelated children with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (CHDFIDD; 617360), Sifrim et al. (2016) identified heterozygous missense mutations in the CDK13 gene (603309.0001-603309.0004). Six of the mutations were proven to have occurred de novo; paternal DNA from the seventh patient was not available, but his mother did not carry the variant. Four patients carried the same mutation (N842S; 603309.0001). All mutations occurred in the highly conserved protein kinase domain, and molecular modeling predicted that the mutations would impair ATP binding, binding of the magnesium ion essential for enzyme activity, or interactions with cyclin K (603544). Six of the patients were ascertained from a cohort of 518 trios in which a child with syndromic congenital heart defects underwent exome sequencing; the seventh patient was 1 of 86 singleton cases. Statistical analysis indicated that de novo missense mutations in the CDK13 gene were significantly enriched in patients compared to those expected under a null mutational model (p = 2.26 x 10(-12), Bonferroni-corrected p = 0.05). Functional studies of the variants and studies of patient cells were not performed.
In 9 patients with CHDFIDD, Bostwick et al. (2017) identified heterozygous pathogenic variants in the CDK13 gene. Two patients had novel CDK13 missense mutations (e.g., N842D; 603309.0005), while the other 7 had the previously identified recurrent variant N842S (603309.0001). The authors also reviewed 20 previously reported patients with CDK13 pathogenic variants. Of the total of 29 patients with CDK13 pathogenic variants, mutations in 27 were de novo and in 2 were of unknown inheritance due to parental samples being unavailable. All variants were missense mutations predicted to impact the protein kinase domain, with clustering in the ATP-binding and magnesium binding sites. More than half (15/29) affected asparagine-842, (14 patients with N842S, 603309.0001 and 1 patient with N842D, 603309.0005), suggesting its importance in magnesium binding. The authors noted that the clustering of missense mutations within a single protein domain and the lack of loss-of-function variants is consistent with a possible gain-of-function mechanism.
Hamilton et al. (2018) reported 9 additional unrelated patients with CHDFIDD associated with de novo heterozygous mutations in the CDK13 gene that were identified by whole-exome sequencing (see, e.g., 603309.0001-603309.0002; 603309.0005-603309.0006). Aside from 1 patient with a splice site mutation, all mutations were missense substitution affecting highly conserved residues. All mutations, including the splice site mutation, occurred within the protein kinase domain, and none were found in the gnomAD database. Molecular modeling and structural analysis indicated that all the missense variants would cause changes to bonding and/or structure that would likely lead to significant loss of catalytic activity. Hamilton et al. (2018) postulated a dominant-negative effect wherein the mutant missense variants would sequester cyclin K into inactive complexes or compete with active complexes for binding to substrates. In vitro functional expression studies of the variants were not performed.
In 3 unrelated children with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (CHDFIDD; 617360), Sifrim et al. (2016) identified a de novo heterozygous c.2525A-G transition (c.2525A-G, NM_031267.3) in the CDK13 gene, resulting in an asn842-to-ser (N842S) substitution in the highly conserved protein kinase domain. A fourth patient with the disorder also carried this heterozygous variant: paternal DNA was not available, but his mother did not carry the variant.
In 7 patients with CHDFIDD, Bostwick et al. (2017) identified a heterozygous N842S mutation. The mutation occurred de novo in all except 1, in whom inheritance was unknown due to parental samples being unavailable.
Hamilton et al. (2018) identified a de novo heterozygous N842S mutation in a patient (patient 11) with CHDFIDD. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that the variant would result in altered catalytic function with a dominant-negative effect.
In a 7.8-year-old boy with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (CHDFIDD; 617360), Sifrim et al. (2016) identified a de novo heterozygous c.2149G-A transition (c.2149G-A, NM_031267.3) in the CDK13 gene, resulting in a gly717-to-arg (G717R) substitution in the highly conserved protein kinase domain.
Hamilton et al. (2018) identified a de novo heterozygous G717R mutation in a patient (patient 3) with CHDFIDD. The patient was mosaic for the mutation. Functional studies of the variant were not performed, but molecular modeling predicted that the variant would result in altered catalytic function with a dominant-negative effect.
In a 5-year-old girl with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (CHDFIDD; 617360), Sifrim et al. (2016) identified a de novo heterozygous c.2140G-C transversion (c.2140G-C, NM_031267.3) in the CDK13 gene, resulting in a gly714-to-arg (G714R) substitution in the highly conserved protein kinase domain.
In a 12-year-old girl with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (CHDFIDD; 617360), Sifrim et al. (2016) identified a de novo heterozygous c.2252G-A transition (c.2252G-A, NM_031267.3) in the CDK13 gene, resulting in an arg751-to-gln (R751Q) substitution in the highly conserved protein kinase domain.
In a 2-year-old girl (patient 1001) with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (CHDFIDD; 617360), Bostwick et al. (2017) identified a heterozygous de novo c.2524A-G transversion in the CDK13 gene that resulted in an asn842-to-asp (N842D) substitution.
In a 10-year-old girl (patient 12) with CHDFIDD, Hamilton et al. (2018) identified a de novo heterozygous mutation in the CDK13 gene, resulting in an asn842-to-asp (N842D) substitution at a highly conserved residue in the protein kinase domain. The mutation was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that the variant would result in altered catalytic function with a dominant-negative effect.
In an 8-year-old girl (patient 14) with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (CHDFIDD; 617360), Hamilton et al. (2018) identified a de novo heterozygous mutation in the CDK13 gene, resulting in a val874-to-leu (V874L) substitution at a highly conserved residue in the activation loop within the protein kinase domain. The mutation was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that the variant would result in altered catalytic function with a dominant-negative effect.
Blazek, D., Kohoutek, J., Bartholomeeusen, K., Johansen, E., Hulinkova, P., Luo, Z., Cimermancic, P., Ule, J., Peterlin, B. M. The cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes Dev. 25: 2158-2172, 2011. [PubMed: 22012619] [Full Text: https://doi.org/10.1101/gad.16962311]
Bostwick, B. L., McLean, S., Posey, J. E., Streff, H. E., Gripp, K. W., Blesson, A., Powell-Hamilton, N., Tusi, J., Stevenson, D. A., Farrelly, E., Hudgins, L., Yang, Y., and 21 others. Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders. Genome Med. 9: 73, 2017. [PubMed: 28807008] [Full Text: https://doi.org/10.1186/s13073-017-0463-8]
Gross, M. B. Personal Communication. Baltimore, Md. 6/29/2012.
Hamilton, M. J., Caswell, R. C., Canham, N., Cole, T., Firth, H. V., Foulds, N., Heimdal, K., Hobson, E., Houge, G., Joss, S., Kumar, D., Lampe, A. K. Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability. J. Med. Genet. 55: 28-38, 2018. [PubMed: 29021403] [Full Text: https://doi.org/10.1136/jmedgenet-2017-104620]
Insco, M. L., Abraham, B. J., Dubbury, S. J., Kaltheuner, I. H., Dust, S., Wu, C., Chen, K. Y., Liu, D., Bellaousov, S., Cox, A. M., Martin, B. J. E., Zhang, T., and 13 others. Oncogenic CDK13 mutations impede nuclear RNA surveillance. Science 380: eabn7625, 2023. [PubMed: 37079685] [Full Text: https://doi.org/10.1126/science.abn7625]
Lapidot-Lifson, Y., Patinkin, D., Prody, C. A., Ehrlich, G., Seidman, S., Ben-Aziz, R., Benseler, F., Eckstein, F., Zakut, H., Soreq, H. Cloning and antisense oligodeoxynucleotide inhibition of a human homolog of cdc2 required in hematopoiesis. Proc. Nat. Acad. Sci. 89: 579-583, 1992. [PubMed: 1731328] [Full Text: https://doi.org/10.1073/pnas.89.2.579]
Sifrim, A., Hitz, M.-P., Wilsdon, A., Breckpot, J., Al Turki, S. H., Thienpont, B., McRae, J., Fitzgerald, T. W., Singh, T., Swaminathan, G. J., Prigmore, E., Rajan, D., and 63 others. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nature Genet. 48: 1060-1065, 2016. [PubMed: 27479907] [Full Text: https://doi.org/10.1038/ng.3627]