Exploring Kabuki Syndrome as a Treatable Cause of Intellectual Disability

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DESCRIPTION (provided by applicant): Intellectual disability is common in the US (2% of school-aged children). Despite this, almost no treatment options are available for this heterogeneous group of disorders. In part, treatment development has been halted by the general notion that intellectual disability is not treatable. However, if one could find a subgroup of treatable causes of intellectual disability and demonstrate the ability to treat these in postnaal life, one would help break this general dogma. Preliminary data suggest that two Mendelian disorders of the histone machinery, Kabuki syndrome and Rubinstein-Taybi syndrome, might be treatable causes of intellectual disability in postnatal life. We have demonstrated that a mouse model of Kabuki syndrome has postnatal hippocampal memory defects and these deficiencies appear to improve when the mice are treated in postnatal life with a histone deacetylase inhibitor. Here we propose to create a tetracycline responsive conditional mouse model of Kabuki syndrome. By altering Mll2 gene expression in postnatal life we will test the hypothesis that the hippocampal memory defects we observed in Mll2 (+/-) mice relate to an ongoing postnatal imbalance between the systems that remove and add H3K4 trimethylation. This model will allow us to test the hypothesis that treatments at different time points in postnatal life are equally effective at treating the hippocampal memory defect found in these syndromes. Together, these experiments would help establish Kabuki syndrome as an additional treatable cause of intellectual disability. Since Kabuki syndrome and Rubinstein-Taybi both have hippocampal memory deficiency caused by an abnormality of the histone modification systems that is associated with open chromatin, we hypothesize that they have a shared mechanism. We aim to test this hypothesis by: (a) determining whether both disorders have a deficiency of either biochemical marker of open chromatin (i.e. histone H3K4 trimethylation and histone acetylation); (b) exploring whether the double heterozygote state (Mll2+/- and Cbp+/-) increases the severity of the abnormalities found in Mll2 (+/-); (c) testing the hypothesis that the gene families found to be down-regulated in these two diseases cluster in several critical pathways shared by the two disorders. By understanding the pathogenesis of these disorders one might be able to identify additional treatable causes of intellectual disability, biomarkers of therapeutc efficiency, and novel therapeutic targets. In an effort to expand the repertoire of agents for treatment of these two disorders we have developed two reporter alleles that encode proteins that inform the activity of a particular histone modification systems: one that fluoresces in response to activity of the H3K4 trimethylation system (deficient in Kabuki syndrome), and one that fluoresces in response to activity of the histone acetylation system (deficient in Rubinstein-Taybi syndrome). We intend to use these alleles for the development of assays for high-throughput discovery of therapeutic agents using both patient cells and/or mouse embryonic stem cells from our mice.