KMT2B

KMT2B, or lysine methyltransferase 2B, is a gene that encodes a histone methyltransferase responsible for methylating histone H3 on lysine 4 (H3K4). It belongs to the KMT2/COMPASS family of methyltransferases that regulate transcription by modifying chromatin. KMT2B participates in multi-subunit COMPASS-like complexes that include core components such as WDR5, RBBP5, ASH2L, and DPY30, and associates with other region-specific subunits to target sets of genes.

KMT2B is widely expressed, with notable activity in developing and adult brain tissue. It contributes to regulation of gene programs important for neurodevelopment and neuronal function by promoting H3K4 methylation at active promoters and enhancers, thereby facilitating transcriptional activation.

Pathogenic variants in KMT2B cause a spectrum of neurodevelopmental disorders, most prominently childhood-onset dystonia (KMT2B-related dystonia). Affected individuals may have developmental delay or intellectual disability, speech impairment, and, less commonly, seizures or autistic features. Most reported cases arise from de novo heterozygous variants; haploinsufficiency due to truncating deletions or nonsense variants is a common mechanism, while missense variants can also produce a similar phenotype.

Clinical management and prognosis: Onset is typically in early childhood, with focal or generalized dystonia that can progress and affect multiple body regions. Diagnosis is usually via genetic sequencing (exome/genome or targeted panels). Management is multidisciplinary, including botulinum toxin injections for focal dystonia, various oral medications to reduce dystonia, and, in selected cases, deep brain stimulation. The prognosis is variable and depends on the severity of dystonia and associated neurodevelopmental features.

Research: Animal models and human studies show that KMT2B-related haploinsufficiency alters global and gene-specific H3K4 methylation, affecting neuronal gene expression. Ongoing work seeks targeted epigenetic therapies or optimization of DBS for KMT2B-associated dystonia.