A mouse model of Kabuki syndrome demonstrates defective hippocampal neurogenesis rescued with treatment with AR-42, a histone deacetylase inhibitor. HT. Bjornsson1, JS. Benjamin1, L. Zhang1, EE. Gerber1, Y. Chen1, MC. Potter2, HC. Dietz1,3 1) McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD; 2) Brain Science Institute, Department of Neurology; 3) Howard Hughes Medical Institute, Baltimore, MD.

   Kabuki syndrome (KS) is caused by heterozygous loss of function mutations in either of two genes with complementary functions, the mixed lineage leukemia 2 (MLL2) and the lysine-specific demethylase 6A (KDM6A) genes. MLL2 is a histone H3K4 methyltransferase that adds trimethylation to H3K4 (an open chromatin mark) while KDM6A is a demethylase that removes trimethylation at H3K27 (a closed chromatin mark). A possible hypothesis for the observed gene dosage sensitivity in Kabuki syndrome would be that the pathogenic sequence is dependent upon a relative imbalance between open and closed chromatin states for critical target genes. If this is the case, it may be possible to restore this balance with drugs that promote open chromatin states, such as histone deacetylase inhibitors (HDACi). In an effort to test this hypothesis we have characterized a novel mouse model of KS with a deletion of the SET domain of Mll2 (Mll2+/Geo). Using an antibody against the trimethylated form of H3K4 we have been able to demonstrate a global deficiency of H3K4 trimethylation in the dentate gyrus of Mll2+/Geo animals compared to wild-type (Mll2+/+) littermates (P<0.005, N=14). Additionally, Mll2+/Geo mice have smaller dentate gyrus volume (P<0.05, N=9) in association with a deficiency of neurogenesis, as evidenced by a deficiency of doublecortin positive proliferating neurons (P<0.05, N=8). Mll2+/Geo mice perform poorly in Morris water maze testing (P<0.05, N=52), suggesting hippocampal memory defects. There is also a deficiency of both H3K4 trimethylation and H4 histone acetylation activity in mouse embryonic fibroblasts from Mll2+/Geo mice when compared to Mll2+/+ (P<0.05), as assessed using optimized novel fluorescent reporter alleles that allow quantitative, sensitive, specific and dynamic monitoring of these functions using fluorescence-activated cell sorting (FACS) of living cells. These deficiencies in cell culture can be ameliorated upon treatment with HDACi (P<0.05). In vivo, the deficiency of H3K4 trimethylation in the dentate gyrus is improved upon treatment with the HDACi AR-42 (P<0.05) in association with a dose-dependent rescue of neurogenesis (with full normalization at 10 mg/kg/day) for both one month and five month old mice. Our work suggests that a reversible deficiency of adult neurogenesis underlies intellectual disability in Kabuki syndrome and provides both rationale and incentive to test novel therapeutic strategies for KS and related disorders.

You may contact the first author (during and after the meeting) at