Exploring Kabuki Syndrome as a Treatable Cause of Intellectual Disability

描述（由申请人提供）：智力残疾在美国很常见（2%的学龄儿童）。尽管如此，几乎没有治疗方案可用于这种异质性疾病组。在某种程度上，治疗方法的发展因智力残疾不可治疗的普遍观念而停止。然而，如果能找到一个子群 智力残疾的可治疗原因，并证明有能力在产后生活中治疗这些疾病，人们将有助于打破这一普遍教条。初步数据表明，两种孟德尔式的组蛋白机制紊乱，歌舞伎综合征和鲁宾斯坦-泰比综合征，可能是出生后智力残疾的可治疗原因。我们已经证明，歌舞伎综合征的小鼠模型具有出生后海马记忆缺陷，并且当小鼠在出生后的生活中用组蛋白去乙酰化酶抑制剂治疗时，这些缺陷似乎得到改善。在这里，我们建议建立一个四环素反应的条件性歌舞伎综合征小鼠模型。通过改变M112基因在出生后的表达，我们将测试我们在M112（+/-）小鼠中观察到的海马记忆缺陷与去除和添加H3 K4三甲基化的系统之间的持续出生后不平衡有关的假设。这个模型将使我们能够检验这一假设，即在出生后不同时间点的治疗是有效的。 在治疗这些综合征中发现的海马记忆缺陷方面同样有效。总之，这些实验将有助于建立歌舞伎综合征作为一个额外的可治疗的原因，智力残疾。由于Kabuki综合征和Rubinstein-Taybi都有海马记忆缺陷，这是由与开放染色质相关的组蛋白修饰系统异常引起的，我们假设它们有一个共同的机制。我们的目标是通过以下方式来验证这一假设：（a）确定这两种疾病是否缺乏开放染色质的生化标志物（即组蛋白H3 K4三甲基化和组蛋白乙酰化）;（B）探索双杂合子状态是否（M112 +/-和Cbp+/-）增加了在M112（+/-）中发现的异常的严重性;（c）检验在这两种疾病中被发现下调的基因家族聚集在这两种疾病共有的几个关键途径中的假设。通过了解这些疾病的发病机制，人们可能能够确定智力残疾的其他可治疗的原因，治疗效率的生物标志物和新的治疗靶点。为了扩大用于治疗这两种疾病的试剂库，我们开发了两种报告等位基因，其编码告知特定组蛋白修饰系统活性的蛋白质：一种响应于H3 K4三甲基化系统的活性而发荧光（Kabuki综合征中缺乏），另一种响应于组蛋白乙酰化系统的活性而发荧光（Rubinstein-Taybi综合征中缺乏）。我们打算使用这些等位基因的发展，用于高通量发现的治疗剂使用患者细胞和/或小鼠胚胎干细胞从我们的小鼠的测定。

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.