Alt. symbols: TNRC21 | MLL2 | ALR | MLL4 | CAGL114

Approved name: lysine methyltransferase 2D
Alt. names: trinucleotide repeat containing 21, myeloid/lymphoid or mixed-lineage leukemia 2, lysine (K)-specific methyltransferase 2D | histone-lysine N-methyltransferase 2D

Location: 12q13.12: 49018975 - 49060794 (-)
Gene type: protein_coding, 35 transcripts.

Scores: LoFtool: | pLI: 1.00000000 | LOEUF: 0.103

HGNC: 7133

NCBI: 8085, RefSeq: NG_027827.1

Ensembl: ENSG00000167548.18

LRG_ | Status: none

OMIM: 602113

Expression | ProteinAtlas

The KMT2D gene encodes the enzyme lysine-specific methyltransferase 2D (MLL2) that is expressed in many body tissues and organs. MLL2 belongs to the family of histone methyltransferase, which are enzymes that methylate histones (structural proteins that bind to DNA and give chromosomes their shape). By adding a methyl group to histones, histone methyltransferases regulate the activity of certain genes; in the case of MLL2 it appears to activate certain genes that are important for development. The lysine-specific methyltransferase 2D is also believed to act as a tumor suppressor.

Monoallelic mutations in KMT2D cause autosomal dominant Kabuki syndrome 1 (KS1) [OMIM:147920]; previously known as Kabuki makeup syndrome, KMS or Niikawa–Kuroki Syndrome. This is a multi-system developmental disorder featuring a characteristic facial gestalt, skeletal anomalies, dental and hair anomalies, developmental delay, intellectual disability, failure-to-thrive and feeding difficulties, congenital heart defects, renal and genitourinary malformations, and hearing and vision issues. Kabuki patients show a CVID-like immunophenotype characterized by increased susceptibility to infections and have reduced serum immunoglobulin levels, while some additionally suffer from autoimmune manifestations, such as idiopathic thrombocytopenic purpura, hemolytic anaemia, autoimmune thyroiditis, and vitiligo. According to ClinVar, more than 300 mutations in the gene are considered pathogenic, including about 120 nonsense, 160 frameshift, 20 splice-site and a dozen missense variants. The majority of missense mutations affect amino acid residues that belong to the zinc finger domains (e.g. p.Cys1424Ser, p.Cys1383Tyr), the N-terminal FYR domain (e.g. p.Arg5179His), the SET domain (e.g. p.Thr5464Met) or the Zinc ion-binding domain (e.g. p.Ser5498Phe); and they are not found in control individuals. In addition to being considered an early driver mutation of lymphomagenesis, KMT2D mutations have also been associated with lymphoproliferative disease in Kabuki patients, likely in the setting of abnormal B cell development (PMID: 30569626, 30282051, 29846842, 26366712, 26366710, 26194542, 24362818, 22372173, 21796119). [Load More]