Alternative titles; symbols
HGNC Approved Gene Symbol: KMT2D
SNOMEDCT: 313426007;
Cytogenetic location: 12q13.12 Genomic coordinates (GRCh38) : 12:49,018,978-49,060,794 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.12 | Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome | 620186 | Autosomal dominant | 3 |
| Kabuki syndrome 1 | 147920 | Autosomal dominant | 3 |
The SET domain is a motif characteristic of proteins such as human ALL1 (159555) and Drosophila 'trithorax' (trx) and is found at the C terminus of the 2 proteins. Using the ALL1 SET domain as a probe, Prasad et al. (1997) cloned a novel gene, KMT2D, which they designated ALR (ALL1-related gene). The gene encodes a 5,262-amino acid protein containing a SET domain, 5 PHD fingers, potential zinc fingers, and a long run of glutamines interrupted by hydrophobic residues (mostly leucine). They also detected an alternatively spliced form encoding 4,957 amino acids and lacking an N-terminal zinc finger and PHD finger. Analysis of ALR expression showed that its approximately 18-kb transcript is expressed, like ALL1, in most adult tissues, including a variety of hematopoietic cells, but not in liver. Whole-mount in situ hybridization of early mouse embryos indicated expression of a similar mouse gene in multiple tissues. Based on similarities in structure and expression pattern, Prasad et al. (1997) concluded that ALR is likely to play a role similar to those of ALL1 and trx.
By database searching, Karlin et al. (2002) identified 192 human protein sequences that have multiple amino acid runs, many of which are associated with disease, including cancer. Karlin et al. (2002) found that a key aspect of 82 of these protein sequences is their role in transcription, translation, and developmental regulation. KMT2D, which Karlin et al. (2002) called MLL2, is a striking example with 24 amino acid runs, all but 2 of which are glutamine runs. Karlin et al. (2002) concluded that genes encoding a significant number of long amino acid runs are potentially associated with disease.
Daniel et al. (2010) showed that activated B cells deficient in the PTIP (608254) component of the MLL3 (606833)-MLL4 complex display impaired 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.
Zhu et al. (2015) demonstrated that p53 (191170) gain-of-function mutants bind to and upregulate chromatin regulatory genes, including the methyltransferases MLL1 (KMT2A; 159555), MLL2 (KMT2D), and acetyltransferase MOZ (KAT6A; 601408), resulting in genomewide increases of histone methylation and acetylation. Analysis of The Cancer Genome Atlas showed specific upregulation of MLL1, MLL2, and MOZ in p53 gain-of-function patient-derived tumors, but not in wildtype p53 or p53-null tumors. Cancer cell proliferation was markedly lowered by genetic knockdown of MLL1 or by pharmacologic inhibition of the MLL1 methyltransferase complex. Zhu et al. (2015) concluded that their study revealed a novel chromatin mechanism underlying the progression of tumors with gain-of-function p53, and suggested possibilities for designing combinatorial chromatin-based therapies for treating individual cancers driven by prevalent gain-of-function p53 mutations.
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, 606834; 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.
Activating mutations in PIK3CA (171834), the gene encoding phosphoinositide-3-kinase-alpha (PI3K-alpha), are frequently found in estrogen receptor (ER; see 133430)-positive breast cancer. PI3K-alpha inhibitors elicit a robust compensatory increase in ER-dependent transcription that limits therapeutic efficacy. Toska et al. (2017) investigated the chromatin-based mechanisms leading to the activation of ER upon PI3K-alpha inhibition and found that PI3K-alpha inhibition mediates an open chromatin state at the ER target loci in breast cancer models and clinical samples. KMT2D, a histone H3 lysine-4 methyltransferase, is required for FOXA1 (602294), PBX1 (176310), and ER recruitment and activation. AKT binds and phosphorylates KMT2D, attenuating methyltransferase activity and ER function, whereas PI3K-alpha inhibition enhances KMT2D activity. Toska et al. (2017) concluded that their findings uncovered a mechanism that controls the activation of ER by the posttranslational modification of epigenetic regulators, providing a rationale for epigenetic therapy in ER-positive breast cancer.
By analysis of rodent/human hybrid cells and analysis of the Genebridge radiation hybrid panel, Prasad et al. (1997) mapped the ALR gene to the 12p13.1-qter region and within a 13-cR chromosome region corresponding to a physical size of approximately 340 kb near D12S1401. Based on information from 3 databases, they placed ALR between vitamin D receptor (601769) at 12q12-q14 and glycerol-3-phosphate dehydrogenase (138420), which is located in the same region. Prasad et al. (1997) noted that the 12q12-q13 region is involved in duplications and translocations associated with cancer.
Kabuki Syndrome 1
Ng et al. (2010) performed the exome sequencing of 10 unrelated patients with Kabuki syndrome (KABUK1; 147920), 7 of European ancestry, 2 of Hispanic ancestry and 1 of mixed European and Haitian ancestry, and identified nonsense or frameshift mutations in the MLL2 gene in 7 patients. Follow-up Sanger sequencing detected MLL2 mutations in 2 of the 3 remaining individuals with Kabuki syndrome and in 26 of 43 additional cases. In all, they identified 33 distinct MLL2 mutations in 35 of 53 families (66%) with Kabuki syndrome (see, e.g., 602113.0001-602113.0004). In each of 12 cases for which DNA from both parents was available, the MLL2 variant was found to have occurred de novo. MLL2 mutations were also identified in each of 2 families in which Kabuki syndrome was transmitted from parent to child. None of the additional MLL2 mutations was found in 190 control chromosomes from individuals of matched geographic ancestry. Ng et al. (2010) suggested that mutations in MLL2 are a major cause of Kabuki syndrome.
Hannibal et al. (2011) identified 70 mutations in the MLL2 gene in 81 (74%) of 110 kindreds with Kabuki syndrome. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, whereas a transmitted mutation was found in 2 of 3 familial cases. Most of the variants were nonsense or frameshift mutations predicted to result in haploinsufficiency. Mutations occurred throughout the gene, but were particularly common in exons 39 and 48. The clinical features of those with or without mutations were similar, except for renal anomalies, which occurred in 47% of mutation carriers compared to 14% of those who did not have a mutation.
Li et al. (2011) sequenced all 54 coding exons of the MLL2 gene in 34 patients with Kabuki syndrome and identified 18 distinct mutations in 19 patients, 11 of 12 tested de novo. Mutations were located throughout the gene and included 3 nonsense mutations, 2 splice site mutations, 6 small deletions or insertions, and 7 missense mutations. Li et al. (2011) compared frequencies of clinical symptoms in MLL2 mutation carriers versus noncarriers. MLL2 mutation carriers more often presented with short stature and renal anomalies (p = 0.026 and 0.031, respectively), and in addition, MLL2 showed a more typical facial gestalt (17 of 19) compared with noncarriers (9 of 15), although this result was not statistically significant (p = 0.1). Mutation-negative patients were subsequently tested for mutations in 10 functional candidate genes, but no convincing causative mutations could be identified. Li et al. (2011) concluded that MLL2 is the major gene for Kabuki syndrome with a wide spectrum of de novo mutations but that there is further genetic heterogeneity accounting for MLL2 mutation-negative patients.
Banka et al. (2012) analyzed the MLL2 gene in a cohort of 116 patients with Kabuki syndrome, including 18 patients previously reported by Hannibal et al. (2011), and identified MLL2 variants in 74 (63.8%). Banka et al. (2012) stated that 170 (73.2%) of 232 published MLL2 mutation-positive kabuki syndrome patients had truncating mutations. They also noted that pathogenic missense mutations were commonly located in exon 48.
Miyake et al. (2013) used mutation detection methods to screen 81 patients with Kabuki syndrome for MLL2 mutations and identified mutations in 50 (61.7%); 35 of the mutations were novel. Most (70%) of the mutations were predicted to be protein-truncating. The truncating mutations were distributed throughout the coding region, whereas the nontruncating mutations were most often within or adjacent to functional domains. Patients with MLL2 truncating mutations had facies that were more typical of those seen in the patients originally reported with Kabuki syndrome. High-arched eyebrows, short fifth fingers and infantile hypotonia were more commonly seen in patients with MLL2 mutations than in those with KDM6A (300128) mutations. Only half of the patients with MLL2 mutations had short stature and postnatal growth retardation, compared to all of the patients with KDM6A mutations.
Using direct sequencing, MLPA, and quantitative PCR, Micale et al. (2014) screened 303 patients with Kabuki syndrome and identified 133 KMT2D mutations, 62 of which were novel. Micale et al. (2014) found that a number of KMT2D truncating mutations result in mRNA degradation through nonsense-mediated mRNA decay, contributing to protein haploinsufficiency. The authors also demonstrated that the reduction of KMT2D protein levels in patients' lymphoblastoid and skin fibroblast cell lines carrying these mutations affects the expression levels of known KMT2D target genes.
Cocciadiferro et al. (2018) evaluated mutations in the KMT2D gene in 505 patients with Kabuki syndrome. A total of 208 mutations in KMT2D were identified in 196 patients. The mutations included 54 nonsense, 59 frameshift, 69 missense, 13 splice site, 12 indels, and 1 large deletion. The missense mutations were distributed across the gene. Cocciadiferro et al. (2018) studied the methylation activity of KMT2D with each of 14 missense mutations, including mutations located in functional N-terminal and C-terminal domains. Nine mutations led to significant impairment of H3K4 monomethylation compared to wildtype, and 2 mutations had borderline effects. In addition, 6 of the mutations led to reduced H3K4me2 and 6 led to reduced H3K4me3.
Daly et al. (2020) identified a de novo heterozygous nonsense mutation in the KMT2D gene (R2099X; 602113.0005) in a patient with KABUK1 who also had holoprosencephaly.
Branchial Arch Abnormalities, Choanal Atresia, Athelia, Hearing Loss, and Hypoparathyroidism Syndrome
In 9 patients from 7 families with branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome, including 2 sibs previously reported by Al-Gazali et al. (2002), Cuvertino et al. (2020) identified heterozygous mutations in exons 38 or 39 of the KMT2D gene (602113.0006-602113.0009). Recombinant KMT2D with each of the mutations did not have abnormal H3K4 trimethylation activity but had a perturbed secondary structure. Methylation profiles of peripheral blood from 4 of the patients with BCAHH were distinct from methylation profiles observed in 4 patients with Kabuki syndrome (see 147920) and 4 patients with CHARGE syndrome (241800), suggesting that these are each epigenetically distinct disorders. Methylated CpG sites in peripheral blood from patients with BCAHH were enriched for CpG sites corresponding to genes associated with head morphology, embryonic development, cell proliferation, and body axis development. Patients with BCAHH did not meet clinical criteria for Kabuki syndrome and had distinct clinical features.
In 4 unrelated patients with BCAHH, including a patient previously reported by Sakata et al. (2017), Baldridge et al. (2020) identified de novo heterozygous missense mutations in the KMT2D gene (see, e.g., 602113.0006; 602113.0010-602113.0011). The mutations were identified by whole-exome sequencing. Functional studies were not performed.
Somatic Mutations
Parsons et al. (2011) identified inactivating mutations in the MLL2 gene in approximately 10% of sequenced medulloblastomas from children.
Morin et al. (2011) found that somatic mutations in MLL2 were present in 32% of diffuse large B-cell lymphomas and 89% of follicular lymphoma cases.
Lee et al. (2013) found that Mll4 (Kmt2d)-knockout mice showed lethality at embryonic day 9.5. Mice with a conditional deletion of Mll4 in somitic precursor cells that give rise to both brown adipose tissue (BAT) and skeletal muscle in the back showed marked decreases in BAT and muscle mass and died immediately after birth due to a breathing malfunction. Chromatin immunoprecipitation assays showed that Mll4 colocalized with lineage-determining transcription factors on active enhancers during differentiation of adipocytes and myocytes. Deletion of Mll4 decreased mono- and dimethylation on lys4 of H3 (see 602810), acetylation of lys27 of H3, and levels of mediator (see MED1, 604311) and polymerase II (see 180660) on enhancers, leading to severe defects in cell type-specific gene expression and cell differentiation. Lee et al. (2013) concluded that MLL4 is a major mammalian H3K4 mono- and dimethyltransferase that is essential for enhancer activation during cell differentiation.
Van Laarhoven et al. (2015) used morpholino antisense oligonucleotides to knock down Kmt2d in zebrafish, and at 5 days postfertilization they observed significant craniofacial defects with severe hypoplasia of the viscerocranium, including complete loss of branchial arches 3 to 7 and Meckel and ceratohyal cartilage; the bony cleithrum and opercles were commonly absent as well. When these structures were present, they were often incompletely formed or clefted. In addition, at 48 hours postfertilization Kmt2d morphants exhibited abnormal development of the atria and/or ventricle as well as prominent bulging of the myocardial wall, and progression through cardiac looping morphogenesis was significantly lower than that observed with wildtype. When compared with wildtype embryos, cross-sectional areas of morphant brains were notably reduced and had a reduced cell layer thickness within the hypothalamus, optic tectum, and midbrain tegmentum. Analysis of neural precursor cell (NPC) markers demonstrated that morphant NPCs are defective in their ability to differentiate in the forebrain and midbrain; the differentiation defects were not observed in the hindbrain.
The KMT2D and KMT2B (606834) genes have both been referred to as MLL2 and MLL4 in the literature.
In 2 unrelated patients with Kabuki syndrome-1 (KABUK1; 147920), Ng et al. (2010) identified a heterozygous 15536G-A transition in the MLL2 gene, resulting in an arg5179-to-his (R5179H) substitution.
In an affected parent and child with Kabuki syndrome-1 (KABUK1; 147920), Ng et al. (2010) identified a heterozygous 13580A-T transversion in the MLL2 gene, resulting in a lys4527-to-ter (K4527X) substitution.
In 2 unrelated patients with Kabuki syndrome-1 (KABUK1; 147920), Ng et al. (2010) identified a heterozygous 16360C-T transition in the MLL2 gene, resulting in an arg5454-to-ter (R5454X) substitution.
In an affected parent and child and an unrelated patient with Kabuki syndrome-1 (KABUK1; 147920), Ng et al. (2010) identified a heterozygous 16391C-T transition in the MLL2 gene, resulting in a thr5464-to-met (T5464M) substitution.
In a 2-year-old girl with Kabuki syndrome-1 (KABUK1; 147920), Daly et al. (2020) identified a de novo heterozygous c.6295C-T transition in the KMT2D gene, resulting in an arg2099-to-ter (R2099X) substitution. The mutation was identified by trio whole-exome sequencing. The patient also had lobar holoprosencephaly.
In 2 unrelated patients (families 1 and 2) with branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH; 620186), Cuvertino et al. (2020) identified heterozygosity for a c.10582C-G transversion (c.10582C-G, NM_003482.3) in exon 38 of the KMT2D gene, resulting in a leu3528-to-val (L3528V) substitution at a highly conserved residue. The mutation, which was identified by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The variant was not present in the gnomAD database. Recombinant KMT2D with the L3528V mutation did not have disturbed H3K4 trimethylation activity but had a perturbed secondary structure.
In a patient (patient 2) with BCAHH, Baldridge et al. (2020) identified heterozygosity for the L3528V mutation in the KMT2D gene. The mutation was found by whole-exome sequencing and was shown to be de novo. The variant was not present in the ExAC and gnomAD databases.
In a patient (family 3) with branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH; 620186), Cuvertino et al. (2020) identified heterozygosity for a c.10625T-C transition (c.10625T-C, NM_003482.3) in exon 38 of the KMT2D gene, resulting in a leu3542-to-pro (L3542P) substitution at a highly conserved residue. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in the gnomAD database. Recombinant KMT2D with the L3542P mutation did not have disturbed H3K4 trimethylation activity but had a perturbed secondary structure.
In 3 patients, including a sib pair in family 4, previously reported by Al-Gazali et al. (2002), and an unrelated patient (family 5), with branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH; 620186), Cuvertino et al. (2020) identified heterozygosity for a c.10658G-T transversion (c.10658G-T, NM_003482.3) in exon 38 of the KMT2D gene, resulting in a gly3553-to-val (G3553V) substitution at a highly conserved residue. The mutation was identified by next-generation sequencing and confirmed by Sanger sequencing. In the proband from family 5, the mutation was de novo. In the 2 sibs from family 4, the mutation was inherited from their mosaic father. There was a similarly affected sib in family 4 who was deceased and did not undergo genetic testing. The mutation was not present in the gnomAD database. Recombinant KMT2D with the G3553V mutation did not have disturbed H3K4 trimethylation activity but had a perturbed secondary structure.
In a mother and son (family 6) and an unrelated patient (family 7) with branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH; 620186), Cuvertino et al. (2020) identified heterozygosity for a c.10745G-A transition (c.10745G-A, NM_003482.3) in exon 39 of the KMT2D gene, resulting in an arg3582-to-gln (R3582Q) substitution at a highly conserved residue. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing in family 6, and by direct gene sequencing in the patient in family 7, segregated with the disorder in both families. The mutation was not present in the gnomAD database. Recombinant KMT2D with the G3553V mutation did not have disturbed H3K4 trimethylation activity but had a perturbed secondary structure.
In a patient (patient 1) with branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH; 620186), Baldridge et al. (2020) identified a de novo heterozygous c.10574T-C transition (c.10574T-C, NM_003482.3) in the KMT2D gene, resulting in a leu3525-to-pro (L3525P) substitution. The mutation was identified by trio whole-exome sequencing. The variant was not present in the ExAC and gnomAD databases.
In a patient (patient 3) with branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH; 620186), Baldridge et al. (2020) identified a de novo heterozygous c.10621G-C transversion (c.10621G-C, NM_003482.3) in the KMT2D gene, resulting in an ala3541-to-pro (A3541P) substitution. The mutation, which was found by whole-exome sequencing, was not present in the ExAC and gnomAD databases.
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