Alternative titles; symbols
HGNC Approved Gene Symbol: KMT2E
Cytogenetic location: 7q22.3 Genomic coordinates (GRCh38) : 7:105,014,205-105,115,019 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q22.3 | O'Donnell-Luria-Rodan syndrome | 618512 | Autosomal dominant | 3 |
The KMT2E gene encodes a member of the lysine N-methyltransferase-2 (KMT2) family, a group of enzymes that play a role in transcriptional regulation through chromatin remodeling (summary by O'Donnell-Luria et al., 2019).
By searching for candidate genes within a commonly deleted segment of chromosome 7q22, followed by database analysis and RT-PCR of bone marrow RNA, Emerling et al. (2002) cloned MLL5. The deduced 1,858-amino acid protein contains an N-terminal PHD finger and a central SET domain. MLL5 shares 38% amino acid identity with MLL (159555), but it lacks the A-T hooks and MT homology domains found in MLL. Northern blot analysis detected a 6.5-kb transcript in all hematopoietic tissues examined. MLL5 expression was also detected in all tissues analyzed on RNA tissue arrays, with the highest levels in fetal thymus and kidney and in adult hematopoietic tissues, jejunum, and cerebellum.
Deng et al. (2004) identified numerous nuclear localization signals distributed throughout the MLL5 sequence. Both transfected epitope-tagged MLL5 and endogenous MLL5 displayed a speckled nuclear distribution and exclusion from nucleoli.
Deng et al. (2004) found that ectopic overexpression of MLL5 induced cell cycle arrest in G1 phase. They hypothesized that MLL5 may form intranuclear protein complexes that may be involved in chromatin remodeling and cellular growth suppression.
Emerling et al. (2002) determined that the MLL5 gene contains 25 exons and spans 73 kb.
By genomic sequence analysis Emerling et al. (2002) mapped the MLL5 gene to chromosome 7q22.
The report of Fujiki et al. (2009), which found that nuclear GlcNAcylation of a histone lysine methyltransferase (HKMT), MLL5, by O-GlcNAc transferase (300255) facilitates retinoic acid-induced granulopoiesis in human HL60 promyelocytes through methylation of H3K4, was retracted.
In 34 individuals with O'Donnell-Luria-Rodan syndrome (ODLURO; 618512), O'Donnell-Luria et al. (2019) identified 31 different heterozygous mutations in the KMT2E gene (see, e.g., 608444.0001-608044.0006). The patients were ascertained through collaboration of several research centers, and the mutations were found by exome or genome sequencing. Most of the mutations resulted in a truncated protein, consistent with haploinsufficiency, although 4 patients carried missense mutations that affected highly conserved residues. The vast majority of the mutations occurred de novo, although there was 1 family with 3 affected sibs who may have inherited the variant from an affected father; DNA from the father was not available. Functional studies of the variants and studies of patient cells were not performed, but the authors postulated haploinsufficiency for KMT2E as the pathogenic mechanism for the protein-truncating mutations, and altered KMT2E binding properties for the missense mutations.
In 18 patients from 17 families with ODLURO, Velmans et al. (2022) identified heterozygous mutations in the KMT2E gene, including 4 nonsense mutations, 7 frameshifts, 2 single nucleotide substitutions involving the canonical splice site, 1 multinucleotide deletion spanning the canonical splice site, and 1 apparent synonymous mutation that was predicted to create a novel splice donor site (608444.0007). Two patients had microdeletions, a 711-kb deletion encompassing approximately 98% of the coding sequence, and a 61-kb deletion encompassing approximately 75% of the coding sequence. Of all 17 mutations, 13 were confirmed to be de novo, 2 were proven not to be inherited from the mother but the fathers were unable to be tested, and 2 were inherited from fathers. Only one of the mutations (608444.0008) had previously been reported.
In a 4-year-old boy (patient 13) with O'Donnell-Luria-Rodan syndrome (ODLURO; 618512), O'Donnell-Luria et al. (2019) identified a de novo heterozygous c.2452C-T transition (c.2452C-T, NM_182931.2) in the KMT2E gene, resulting in an arg818-to-ter (R818X) substitution. The variant, which was found by whole-exome or whole-genome sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in nonsense-mediated mRNA decay and haploinsufficiency.
In a 9-year-old girl (patient 22) with O'Donnell-Luria-Rodan syndrome (ODLURO; 618512), O'Donnell-Luria et al. (2019) identified a de novo heterozygous c.3554C-G transversion (c.3554C-G, NM_182931.2) in the KMT2E gene, resulting in a ser1185-to-ter (S1185X) substitution. The variant, which was found by whole-exome or whole-genome sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in nonsense-mediated mRNA decay and haploinsufficiency.
In 2 unrelated children (patients 9 and 10) with O'Donnell-Luria-Rodan syndrome (ODLURO; 618512), O'Donnell-Luria et al. (2019) identified a de novo heterozygous 5-bp deletion (c.1776_1780delAAAGA, NM_182931.2) in the KMT2E gene, resulting in a frameshift and premature termination (Lys593ArgfsTer17). The variant, which was found by whole-exome or whole-genome sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in nonsense-mediated mRNA decay and haploinsufficiency.
In 3 brothers (family 3) with O'Donnell-Luria-Rodan syndrome (ODLURO; 618512), O'Donnell-Luria et al. (2019) identified a heterozygous 1-bp duplication (c.450dupT, NM_182931.2) in the KMT2E gene, resulting in a premature termination (arg151-to-ter; R151X) in the PHD finger domain. The variant, which was found by whole-exome or whole-genome sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or gnomAD databases. The variant was not found in the mother; the father, who was not available for testing, was reported to have had intellectual disability. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in nonsense-mediated mRNA decay and haploinsufficiency.
In a 16-year-old boy (patient 33) with O'Donnell-Luria-Rodan syndrome (ODLURO; 618512), O'Donnell-Luria et al. (2019) identified a de novo heterozygous c.418G-A transition (c.418G-A, NM_182931.2) in the KMT2E gene, resulting in a val140-to-ile (V140I) substitution at a highly conserved residue in the PHD finger domain. The variant, which was found by whole-exome or whole-genome sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but the substitution was predicted to change the structure of the protein.
In a 3-year-old girl (patient 35) with O'Donnell-Luria-Rodan syndrome (ODLURO; 618512), O'Donnell-Luria et al. (2019) identified a de novo heterozygous c.2720A-T transversion in the KMT2E gene, resulting in an asp907-to-val (D907V) substitution at a highly conserved residue. The variant, which was found by whole-exome or whole-genome sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but the substitution was predicted to change the structure of the protein.
In a patient (patient 13) with O'Donnell-Luria-Rodan syndrome (ODLURO; 618412), Velmans et al. (2022) identified a de novo heterozygous c.264A-G transition (c.264A-G, NM_182931.2) in the KMT2E gene, predicting to result in a synonymous change (glu88-to-glu) that is predicted to activate a cryptic donor site.
In a patient (patient 10) with O'Donnell-Luria-Rodan syndrome (ODLURO; 618412), O'Donnell-Luria et al. (2019) identified a de novo heterozygous duplication at nucleotide 4829 (c.4829dupT, NM_182931.2) in the KMT2E gene, predicted to result in a frameshift and protein extension (Leu1610PhefsTer259). Velmans et al. (2022) reported another boy with ODLURO who had the same de novo heterozygous mutation. The mutation is predicted to escape nonsense-mediated decay.
Deng, L.-W., Chiu, I., Strominger, J. L. MLL 5 protein forms intranuclear foci, and overexpression inhibits cell cycle progression. Proc. Nat. Acad. Sci. 101: 757-762, 2004. [PubMed: 14718661] [Full Text: https://doi.org/10.1073/pnas.2036345100]
Emerling, B. M., Bonifas, J., Kratz, C. P., Donovan, S., Taylor, B. R., Green, E. D., Le Beau, M. M., Shannon, K. M. MLL5, a homolog of Drosophila trithorax located within a segment of chromosome band 7q22 implicated in myeloid leukemia. Oncogene 21: 4849-4854, 2002. [PubMed: 12101424] [Full Text: https://doi.org/10.1038/sj.onc.1205615]
Fujiki, R., Chikanishi, T., Hashiba, W., Ito, H., Takada, I., Roeder, R. G., Kitagawa, H., Kato, S. GlcNAcylation of a histone methyltransferase in retinoic-acid-induced granulopoiesis. Nature 459: 455-459, 2009. Note: Retraction: Nature 505: 574 only, 2014. [PubMed: 19377461] [Full Text: https://doi.org/10.1038/nature07954]
O'Donnell-Luria, A. H., Pais, L. S., Faundes, V., Wood, J. C., Sveden, A., Luria, V., Abou Jamra, R., Accogli, A., Amburgey, K., Anderlid, B. M., Azzarello-Burri, S., Basinger, A. A., and 74 others. Heterozygous variants in KMT2E cause a spectrum of neurodevelopmental disorders and epilepsy. Am. J. Hum. Genet. 104: 1210-1222, 2019. [PubMed: 31079897] [Full Text: https://doi.org/10.1016/j.ajhg.2019.03.021]
Velmans, C., O'Donnell-Luria, A. H., Argilli, E., Tran Mau-Them, F., Vitobello, A., Chan, M. C., Fung, J. L., Rech, M., Abicht, A., Aubert Mucca, M., Carmichael, J., Chassaing, N., and 27 others. O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum. J. Med. Genet. 59: 697-705, 2022. [PubMed: 34321323] [Full Text: https://doi.org/10.1136/jmedgenet-2020-107470]