The KMT2A gene encodes Lysine-Specific Methyltransferase 2A, a large nuclear protein belonging to the myeloid/lymphoid or mixed-lineage leukemia (MLL) family. The protein functions as an enzyme and is responsible for catalyzing the methylation of the Lysine-4 residue of histone H3, a process required for epigenetic transcriptional activation. KMT2A hence positively regulates the transcription of several target genes such as HOXA9. It is also involved in the control of circadian gene expression, PPP1R15A-induced apoptosis, cell proliferation and haematopoiesis.
The MLL gene is also a frequent target for translocations. These rearrangements can lead to the fusion of the MLL gene with over 50 different partners. The resultant fusion proteins are able to transform hematopoietic cells into leukemia stem cells and hence MLL rearrangements have been implicated in Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL) and Mixed Lineage (biphenotypic) Leukemia (MLL).
Further, mutations in the gene have been associated with Wiedemann-Steiner Syndrome (WDSTS), a multi-system disorder characterized by hypertrichosis cubiti, short stature, intellectual disability and distinct facial dysmorphia. KMT2A mutations have also recently been implicated in Kabuki Syndrome 2 (KABUK2), an intellectual disability condition known for its distinct facies of long palpebral fissures and eversion of the lateral third of the lower eyelid.
The KMT2A gene is located on the long arm of chromosome 11. It spans a length of 90.3 kb of DNA and its coding sequence is contained within 37 exons. The protein product encoded by this gene has a molecular mass of 431.7 kDa and consists of 3969 amino acids. Multiple isoforms of the KMT2A gene exist due to alternatively spliced transcript variants. The gene is widely expressed in the human body, with overexpression seen in the peripheral blood mononuclear cells, adipocyte, B-lymphocyte and CD8 T-cells. Heterozygous de novo mutations in the gene, including deletions and nonsense mutations, have been linked to Wiedemann-Steiner Syndrome.
Monies et al. (2017) reported the findings of 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. One patient, a 4-year-old female, suffered from skeletal dysplasia, ribs fusion, ear deformity, cleft palate, absent uterus and vagina and choanal atresia. The phenotype resembled a CHARGE-like presentation, however, a multigene panel for dysmorphology/skeletal dysplasia identified a de-novo heterozygous mutation (c.3248G>A, p.R1083Q) in exon 4 of the patient’s KMT2A gene, associated with Kabuki syndrome. This case highlighted the benefit of molecular testing in the diagnosis of overlapping clinical syndromes.
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