Kleefstra-like syndrome

EHMT2 (G9a) and EHMT1 (GLP) are highly homologous proteins that mono- and dimethylate lysine 9 on histone H3 (H3K9). H3K9 methylation plays a critical role in development, differentiation, and cancer. Deletions in the EHMT1 gene cause a neurodevelopmental disorder known as Kleefstra syndrome (KS, OMIM # 610253). In contrast, individuals with alterations in the EHMT2 gene are rarely reported but appear to exhibit a phenotype overlapping with KS. More info
SHOW MOUSE MODELS

Kleefstra-like syndrome presents with severe developmental delay, intellectual disability, and autism-like features, accompanied by hyperkinetic hand movements during emotional states, bruxism, and self-mutilation when angry. EEG reveals abnormal focal activity, and MRI shows brain atrophy, occurrence of an arachnoid cyst, and corpus callosum thinning. Motor skills are suboptimal; independent walking is limited to short distances. Additionally, growth and sexual maturation are delayed.

Pathogenic Mechanism

Kleefstra-like syndrome appears to result from mutations in the catalytic SET domain of the EHMT2 protein, impairing its methyltransferase activity. This disruption leads to altered epigenetic landscapes and dysregulated gene expression.

Mouse Models

  • C57BL/6NCrl-Ehmt2em1Ccpcz/Ph (short EADV mutation in SET domain mimicking patient mutation)