Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome

Abstract

Kabuki syndrome is caused by haploinsufficiency for either of two genes that promote the opening of chromatin. If an imbalance between open and closed chromatin is central to the pathogenesis of Kabuki syndrome, agents that promote chromatin opening might have therapeutic potential. We have characterized a mouse model of Kabuki syndrome with a heterozygous deletion in the gene encoding the lysine-specific methyltransferase 2D (Kmt2d), leading to impairment of methyltransferase function. In vitro reporter alleles demonstrated a reduction in histone 4 acetylation and histone 3 lysine 4 trimethylation (H3K4me3) activity in mouse embryonic fibroblasts from Kmt2d+/βGeo mice. These activities were normalized in response to AR-42, a histone deacetylase inhibitor. In vivo, deficiency of H3K4me3 in the dentate gyrus granule cell layer of Kmt2d+/βGeo mice correlated with reduced neurogenesis and hippocampal memory defects. These abnormalities improved upon postnatal treatment with AR-42. Our work suggests that a reversible deficiency in postnatal neurogenesis underlies intellectual disability in Kabuki syndrome.

A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome

“…After 2 wk of treatment with the HDACi AR-42, an antineoplastic agent, we observed normalization of these phenotypes (6) (Fig. S1).…”

“…), we observed a deficiency of adult neurogenesis, a dynamic process during adult life (5), in association with hippocampal memory deficits (6). After 2 wk of treatment with the HDACi AR-42, an antineoplastic agent, we observed normalization of these phenotypes (6) (Fig.…”

“…Our findings that exogenous BHB treatment lead to similar effects on neurogenesis as the KD support the hypothesis that BHB contributes significantly to the therapeutic effect. In our previous study (6), the HDACi AR-42 led to improved performance in the probe trial of the MWM for both Kmt2d +/βGeo and Kmt2d +/+ mice (genotype-independent improvement). In contrast, KD treatment only led to improvement in Kmt2d +/βGeo mice (genotype-dependent improvement).…”

“…Recently, beta-hydroxybutyrate (BHB), a ketone body that is the natural end product of hepatic fatty acid beta oxidation, has been shown to have HDACi activity (7). Because BHB is actively transported into the central nervous system during ketosis (8), and furthermore has been shown to directly enter the hippocampus (9), it should be readily available to modulate histone modifications in relevant cells (neurons); this would be expected to ameliorate the deficiency of adult neurogenesis in Kmt2d +/βGeo mice (6). A dietary intervention could be quickly transitioned to the clinic and is unlikely to have major adverse effects.…”

RAP1-mediated MEK/ERK pathway defects in Kabuki syndrome

“…Likewise, the MAPK pathway is critical in mediating a host of neurodevelopmental processes through the regulation of gene expression, including neurogenesis and neuronal plasticity (43). We speculate that alterations in these MAPK-driven neuronal processes might underlie impaired cognitive development, which could be accessible to postnatal pharmacological treatment in patients with KS (44). Pharmacological MEK/ERK inhibition at neonatal stages was shown to rescue brain anomalies in an animal model of an Nf1-related RASopathy (45).…”