Alternative titles; symbols
HGNC Approved Gene Symbol: KMT2C
Cytogenetic location: 7q36.1 Genomic coordinates (GRCh38) : 7:152,134,925-152,436,003 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q36.1 | Kleefstra syndrome 2 | 617768 | Autosomal dominant | 3 |
The KMT2C gene encodes a histone methyltransferase that regulates gene transcription by modifying chromatin structure. KMT2C mediates mono- and tri-methylation of histone H3 at lysine 4 (H3K4me1 and H3K4me3) (summary by Koemans et al., 2017).
By searching for cDNA sequences with the potential to encode large proteins expressed in brain, Nagase et al. (2000) identified a partial cDNA encoding MLL3, which they termed KIAA1506. RT-PCR analysis detected ubiquitous expression that was highest in testis and ovary, followed by brain and liver. Within brain, expression was highest in hippocampus, caudate nucleus, and substantia nigra.
By genomic sequence analysis combined with RACE and PCR on a fetal thymus cDNA library, Ruault et al. (2002) isolated 3 partial overlapping cDNAs that they assembled to identify MLL3. The deduced 4,911-amino acid protein is more closely related to MLL2 (602113) than to MLL1 (159555) or MLL4 (606834). The authors identified a shorter isoform (isoform II) in the databases that has 4,026 predicted residues due to an alternative 5-prime region. MLL3 has 6 plant homeodomain (PHD) fingers preceded by a cys-rich ZNF1 domain in its N terminus; a high mobility group (HMG) box, an ATPase alpha-beta signature, and a leucine zipper motif in its central region; and 2 C-terminal FY (phe-tyr) motifs and a SET (suppressor of variegation, enhancer of zeste, and trithorax) domain preceded by a ZNF2 domain in its C terminus. The predicted protein also contains several putative nuclear localization motifs. Isoform II lacks ZNF1 and the PHD. Northern blot analysis revealed weak expression of a 15-kb transcript. PCR analysis of a cDNA panel detected expression in all tissues tested except skeletal muscle and fetal liver.
Ruault et al. (2002) determined that the MLL3 gene contains 60 exons and spans more than 216 kb. It is preceded in the 5-prime region by a 1.8-kb CpG island. Isoform II of MLL3 lacks the first 14 exons. The authors found that the 5-prime untranslated region of MLL3 possesses a nonpolymorphic CGG repeat.
Using FISH, Ruault et al. (2002) mapped the MLL3 gene to chromosome 7q36, a region commonly deleted in malignant myeloid disorders. They also identified signals in the juxtacentromeric regions of chromosomes 1, 2, 13, and 21, which probably contain paralogous regions duplicated during primate evolution.
Daniel et al. (2010) showed that activated B cells deficient in the PTIP (608254) component of the MLL3-MLL4 complex display impaired trimethylation of histone H3 (see 602810) at lysine-4 (H3K4me3) and transcription initiation of downstream switch regions at the immunoglobulin heavy chain (Igh; 147100) locus, leading to defective immunoglobulin class switching. Daniel et al. (2010) also showed that PTIP accumulation at double-strand breakpoints contributes to class switch recombination and genome stability independent of Igh switch transcription. Daniel et al. (2010) concluded that their results demonstrated that PTIP promotes specific chromatin changes that control the accessibility of the Igh locus to class switch recombination and suggested a nonredundant role for the MLL3-MLL4 complex in altering antibody effector function.
Li et al. (2016) demonstrated that a minimized human RBBP5 (600697)-ASH2L (604782) heterodimer is the structural unit that interacts with and activates all MLL family histone methyltransferases (MLL1; MLL2; MLL3; MLL4; SET1A, 611052; SET1B, 611055). Their structural, biochemical, and computational analyses revealed a 2-step activation mechanism of MLL family proteins. Li et al. (2016) concluded that their findings provided unprecedented insights into the common theme and functional plasticity in complex assembly and activity regulation of MLL family methyltransferases, and also suggested a universal regulation mechanism for most histone methyltransferases.
In 4 of 9 EHMT1 (607001) mutation-negative patients with core features of Kleefstra syndrome-1 (KLEFS1; 610253) but otherwise heterogeneous phenotypes, Kleefstra et al. (2012) identified mutations in 4 functionally related genes, KMT2C (606833.0001), MBD5 (611472), SMARCB1 (601607), and NR1I3 (603881). All these genes encode epigenetic regulators. The KMT2C mutation was a de novo heterozygous truncating mutation; this patient had a phenotype consistent with Kleefstra syndrome-2 (KLEFS2; 617768).
In 5 additional patients with KLEFS2, Koemans et al. (2017) identified 4 different de novo heterozygous frameshift or truncating mutations in the KMT2C gene (606833.0002-606833.0005). The fifth patient had a de novo heterozygous 203-kb intragenic deletion in the KMT2C gene. All mutations were predicted to result in a loss of function, but specific functional studies of the variants and studies of patient cells were not performed.
Faundes et al. (2018) reported 3 unrelated patients with severely impaired intellectual development associated with de novo heterozygous mutations in the KMT2C gene. The patients had global developmental delay apparent in early infancy, with impaired intellectual development, mildly delayed walking, and poor or absent speech. The first 2 patients were ascertained from a cohort of 4,293 trios from the Deciphering Developmental Disorders (DDD) study who underwent exome sequencing; the third patient was ascertained from another cohort of children with developmental disorders. The KMT2C gene was chosen for study through a pathway-based approach focusing on candidate genes involved in histone lysine methylation/demethylation. The variants were filtered against several large databases, including ExAC, the 1000 Genomes Project, and the Exome Sequencing Project. Functional studies of the variants and studies of patient cells were not performed, but all mutations were predicted to result in a loss of function and haploinsufficiency.
Koemans et al. (2017) found that specific knockdown of 'trr,' the Drosophila ortholog of KMT2C, in the mushroom body of the fly brain resulted in impaired short term memory. Immunoprecipitation studies showed that trr normally localizes in the nucleus of the mushroom body, and that it binds to the promoter of many genes involved in neuronal processes in the fly head. Transcriptional profiling of pan-neuronal trr knockdown and G9a (the ortholog of EHMT1; 607001) null mutant fly heads identified many misregulated genes in both scenarios; these gene sets showed significant overlap and were associated with nearly identical gene ontology enrichments. There were many common indirect target genes and several common direct target genes, including those involved in regulation of synaptic plasticity. The findings delineated the molecular convergence between the KMT2 and EHMT protein families, which may contribute to a molecular network involved in neurodevelopment.
In a girl with Kleefstra syndrome-2 (KLEFS2; 617768), Kleefstra et al. (2012) identified a heterozygous C-to-T transition at nucleotide 4441 of the MLL3 gene that resulted in an arg1481-to-ter substitution (R1481X). The father was not available for testing, but neither the patient's mother nor either of her unaffected sisters (who carried the same paternal haplotype as the patient at the MLL3 locus) carried this mutation.
In a 29-year-old man (patient 1) with Kleefstra syndrome-2 (KLEFS2; 617768), Koemans et al. (2017) identified a de novo heterozygous 1-bp deletion (c.5216del) in the KMT2C gene, resulting in a frameshift and premature termination (Pro1739LeufsTer2). The mutation was found by whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 31-year-old man (patient 2) with Kleefstra syndrome-2 (KLEFS2; 617768), Koemans et al. (2017) identified a de novo heterozygous c.7550C-G transversion in the KMT2C gene, resulting in a ser2517-to-ter (S2517X) substitution. The mutation was found by whole-exome sequencing. The patient appeared to be mosaic for the mutation, as it was found in about 30% of peripheral blood cells. Functional studies of the variant and studies of patient cells were not performed.
In a 15-year-old boy (patient 3) with Kleefstra syndrome-2 (KLEFS2; 617768), Koemans et al. (2017) identified a de novo heterozygous c.1690A-T transversion in the KMT2C gene, resulting in a lys564-to-ter (K564X) substitution. The mutation was found by whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
In a 7-year-old girl (patient 4) with Kleefstra syndrome-2 (KLEFS2; 617768), Koemans et al. (2017) identified a de novo heterozygous 4-bp deletion (c.10812_10815del) in the KMT2C gene, resulting in a frameshift and premature termination (Lys3605GlufsTer24). The mutation was found by whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
Daniel, J. A., Santos, M. A., Wang, Z., Zang, C., Schwab, K. R., Jankovic, M., Filsuf, D., Chen, H.-T., Gazumyan, A., Yamane, A., Cho, Y.-W., Sun, H.-W., Ge, K., Peng, W., Nussenzweig, M. C., Casellas, R., Dressler, G. R., Zhao, K., Nussenzweig, A. PTIP promotes chromatin changes critical for immunoglobulin class switch recombination. Science 329: 917-923, 2010. [PubMed: 20671152] [Full Text: https://doi.org/10.1126/science.1187942]
Faundes, V., Newman, W. G., Bernardini, L., Canham, N., Clayton-Smith, J., Dallapiccola, B., Davies, S. J., Demos, M. K., Goldman, A., Gill, H., Horton, R., Kerr, B., and 11 others. Histone lysine methylases and demethylases in the landscape of human developmental disorders. Am. J. Hum. Genet. 102: 175-187, 2018. [PubMed: 29276005] [Full Text: https://doi.org/10.1016/j.ajhg.2017.11.013]
Kleefstra, T., Kramer, J. M., Neveling, K., Willemsen, M. H., Koemans, T. S., Vissers, L. E. L. M., Wissink-Lindhout, W., Fenckova, M., van den Akker, W. M. R., Nadif Kasri, N., Nillesen, W. M., Prescott, T., and 10 others. Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Am. J. Hum. Genet. 91: 73-82, 2012. [PubMed: 22726846] [Full Text: https://doi.org/10.1016/j.ajhg.2012.05.003]
Koemans, T. S., Kleefstra, T., Chubak, M. C., Stone, M. H., Reijnders, M. R. F., de Munnik, S., Willemsen, M. H., Fenckova, M., Stumpel, C. T. R. M., Bok, L. A., Saenz, M. S., Byerly, K. A., Baughn, L. B., Stegmann, A. P. A., Pfundt, R., Zhou, H., van Bokhoven, H., Schenck, A., Kramer, J. M. Functional convergence of histone methyltransferases EHMT1 and KMT2C involved in intellectual disability and autism spectrum disorder. PLoS Genet. 13: e1006864, 2017. Note: Electronic Article. [PubMed: 29069077] [Full Text: https://doi.org/10.1371/journal.pgen.1006864]
Li, Y., Han, J., Zhang, Y., Cao, F., Liu, Z., Li, S., Wu, J., Hu, C., Wang, Y., Shuai, J., Chen, J., Cao, L., Li, D., Shi, P., Tian, C., Zhang, J., Dou, Y., Li, G., Chen, Y., Lei, M. Structural basis for activity regulation of MLL family methyltransferases. Nature 530: 447-452, 2016. [PubMed: 26886794] [Full Text: https://doi.org/10.1038/nature16952]
Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 143-150, 2000. [PubMed: 10819331] [Full Text: https://doi.org/10.1093/dnares/7.2.143]
Ruault, M., Brun, M. E., Ventura, M., Roizes, G., De Sario, A. MLL3, a new human member of the TRX/MLL gene family, maps to 7q36, a chromosome region frequently deleted in myeloid leukaemia. Gene 284: 73-81, 2002. [PubMed: 11891048] [Full Text: https://doi.org/10.1016/s0378-1119(02)00392-x]