Kabuki Syndrome

Kabuki Syndrome and Cancer

KMT2D codes for a histone methyl transferase that catalyses the monomehtylation of lysine 4 on histone H3 (H3K4me1), defining mark of transcriptional enhancers. Recently, KMT2D has emerged as one of the most frequently mutated genes across a wide spectrum of cancers, with a driver role in the majority of them. Moreover, acute deletion of KMT2D has been associated with genomic instability selectively affecting actively transcribed genes, providing a suggestive link between its enhancer marking function and the preservation of genome integrity. Strikingly, KMT2D germline mutations (often affecting the same residues mutated in tumors) cause Kabuki syndrome (KS), a multisystemic neurodevelopmental disorder with no apparent cancer predisposition but that affects the development of several organ systems and tissues. Thus, KMT2D represents a paradigmatic example of the cell type and context dependent impact of oncogenic mutations, with germline mutations thought to trigger compensatory effects that set in early and suppress their tumorigenic potential.

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