Alt. symbols: MLL | TRX1 | HRX | ALL-1 | HTRX1 | CXXC7 | MLL1A

Approved name: lysine methyltransferase 2A
Alt. names: myeloid/lymphoid or mixed-lineage leukemia (trithorax (Drosophila) homolog), myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila), lysine (K)-specific methyltransferase 2A | Histone-lysine N-methyltransferase 2A

Location: 11q23.3: 118436456 - 118526832 (+)
Gene type: protein_coding, 34 transcripts.

Scores: LoFtool: | pLI: 1.00000000 | LOEUF: 0.065

HGNC: 7132

NCBI: 4297, RefSeq: NG_027813.1

Ensembl: ENSG00000118058.25

LRG_613 | Status: public

OMIM: 159555

Expression | ProteinAtlas

This gene encodes a transcriptional coactivator (Histone methyltransferase, MLL) that plays an essential role in regulating gene expression during early development and hematopoiesis. MLL is the catalytic subunit of the MLL1/MLL complex, which mediates both methylation of ‘Lys-4’ of histone H3 (H3K4me) complex and acetylation of ‘Lys-16’ of histone H4 (H4K16ac). In the MLL1/MLL complex, it specifically mediates H3K4me, a specific tag for epigenetic transcriptional activation (PMID:12453419, PMID:20677832, PMID:26886794).

Monoallelic loss-of-function mutations in the gene have been associated with Wiedemann-Steiner syndrome (WSS) [MIM:605130]. KMT2A haploinsufficiency causes a complex syndrome characterized by dysmorphic facial features (e.g. hypertelorism, palpebral fissures), musculoskeletal (e.g. short stature, tapering fingers), gastrointestinal, cutaneous (e.g. hairy elbows), and behavioral abnormalities (e.g. aggressive behaviour) or intellectual disability. Pathogenic variants associated with WSS include s mall deletions and insertions, stop-gained mutations (p.Lys1534*, p.Gln2261*, p.Leu2756*, p.Arg2382*, p.Arg2480*) and missense mutations (p.Pro280Thr, p.Cys1161Gly, p.Cys1189Tyr, p.Cys1448Arg). The missense variant p.Cys1161Gly was found in a 14 year old male patient with a complex phenotype overlapping WSS, who also exhibited epilepsy, microcephaly, and congenital immunodeficiency. He presented with low immunoglobulin levels and urinary tract infections (Stellacci et al., 2016). Two further missense variants (p.Cys1189Tyr and p.Pro280Thr) were detected in two patients of age 4 with features of WSS (Miyake et al., 2016). In addition, two cases of atypical WSS with a phenotype being not fully developed were reported to be caused by missense (p.Cys1448Arg) or splice site (c.4086+G>A) variants (Strom et al., 2014). However, all four missense mutations described to date were only reported based on clinical and genetic findings, but the effects of the variants on protein function and abundancy was not functionally examined. In addition to the four cases with missense mutations in KMT2A, three other individuals (two twins and their mother) were described. All three were initially misdiagnosed with early-onset common variable immunodeficiency, because extra-immunological features (musculoskeletal, craniofacial, neurological and internal organ anomalies) were subtle and only became conspicuous with age (Bogaert, D. et al., 2017). The family carried the c.10835+1G>A splice-site mutation, which resulted in skipping of exon 28. In addition to the association with WSS, multiple chromosomal rearrangements involving KMT2A are the cause of certain acute lymphoid leukemias and acute myeloid leukemias (Forgione et al., 2019, Sakhdari et al., 2019). [Load More]