Loss of Function of KMT2D in MLL4 Complex Formation in Kabuki Syndrome

The entire C-terminal region of histone-lysine-N-methyltransferase KMT2D (residues 4507-5537), which includes the ZF, PHD7, FYRN, FYRC, WIN and SET domains, is involved in binding to the WRAD complex. Missense mutations in the C-terminal region of KMT2D, identified in Kabuki syndrome patients, affect its binding to the WRAD complex, consisting of WDR5, RBBP5, ASH2L and DPY30. While the impact of KMT2D truncating mutations on the WRAD complex binding has not been tested, they were shown to frequently result in KMT2D mRNA degradation through nonsense-mediated mRNA decay and contribute to haploinsufficiency.

Summary from Reactome (R-HSA-9944997), read 2026-09-23.