Premium
Kabuki syndrome missense mutations disrupt the formation and histone methyltransferase activity of the MLL2 core complex
Author(s) -
Shinsky Stephen Alan,
Hu Michael,
Vought Valarie E,
Ng Sarah B,
Bamshad Michael J,
Shendure Jay,
Cosgrove Michael S
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.772.1
Subject(s) - missense mutation , genetics , biology , histone methyltransferase , histone , gene , kabuki syndrome , methylation , nonsense mutation , mutation
Kabuki syndrome (KS) is a rare disorder characterized by multiple malformations and cognitive delay. Recent studies reveal that ~70% of KS individuals have missense or nonsense mutations in coding regions of the Mixed‐Lineage Leukemia 2 (MLL2 or ALR) gene. MLL2 catalyzes histone 3 lysine 4 (H3K4) methylation using a conserved SET domain in complex with WDR5, RbBP5, ASH2L and DPY30 (WRAD), together forming what is known as the MLL2 core complex. H3K4 methylation is required for transcription of genes involved in normal development. In KS, the majority of nonsense mutations delete the SET domain, while most missense mutations localize in or near the SET domain. This suggests that KS may result from a loss of function of MLL2 SET domain activity. To test this hypothesis, we substituted conserved amino acid positions in the closely related MLL1 homolog with KS missense mutations and found that all alter enzymatic activity, but in distinct ways. The R5340L variant does not complex with WRAD and loses H3K4 dimethylation activity. The R5471T, G5428D and T5464M variants form atypical complexes with WRAD, but with a weakened interaction with ASH2L. As a result, the R5471T and G5428D variants are enzymatically inactive, whereas the T5464M variant is defective for H3K4 dimethylation. Our results are consistent with the hypothesis that KS results from loss of MLL2 enzymatic activity. Work supported by NIH Grant #R01CA140522 to M.S.C.