Exploring Kabuki Syndrome as a Treatable Cause of Intellectual Disability

描述(由申请人提供)：智力障碍在美国很常见(占学龄儿童的2%)。尽管如此，对于这类异质性疾病，几乎没有可用的治疗选择。在某种程度上，由于普遍认为智力残疾是不可治疗的，治疗方法的开发已经停止。然而，如果有人能找到一个子群 对智力残疾的可治疗原因进行分析，并展示出在产后生活中治疗这些疾病的能力，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障碍，歌舞伎综合征和鲁宾斯坦-塔比综合征，可能是出生后智力残疾的可治疗原因。我们已经证明，歌舞伎综合症的小鼠模型存在出生后海马区记忆缺陷，当小鼠出生后使用组蛋白脱乙酰酶抑制剂治疗时，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性条件小鼠歌舞伎综合症模型。通过改变出生后生活中MLL2基因的表达，我们将检验这一假设，即我们在MLL2(+/-)小鼠中观察到的海马体记忆缺陷与移除和添加H3K4三甲基化的系统之间持续的出生后失衡有关。这个模型将允许我们检验在出生后生活的不同时间点进行治疗的假设 在治疗这些综合征中发现的海马体记忆缺陷方面同样有效。总而言之，这些实验将有助于将歌舞伎症确立为智力残疾的另一种可治疗原因。由于歌舞伎综合征和Rubinstein-Taybi都有与开放染色质相关的组蛋白修饰系统异常导致的海马区记忆缺陷，我们假设他们有共同的机制。我们旨在通过以下方式检验这一假说：(A)确定这两种疾病是否都缺乏开放染色质的生化标记物(即组蛋白H3K4三甲基化和组蛋白乙酰化)；(B)探索双重杂合子状态(MLL2+/-和CBP+/-)是否增加了MLL2(+/-)中发现的异常的严重性；(C)检验在这两种疾病中发现下调的基因家族聚集在两种疾病共有的几条关键途径中的假设。通过了解这些疾病的发病机制，人们可能能够确定其他可治疗的智力残疾原因、治疗效果的生物标记物和新的治疗靶点。为了扩大治疗这两种疾病的药物的范围，我们开发了两个报告等位基因，它们编码通知特定组蛋白修饰系统活性的蛋白质：一个响应H3K4三甲基化系统的活性(歌舞伎症缺乏)而荧光，一个响应组蛋白乙酰化系统的活性(鲁宾斯坦-塔比综合征缺乏)。我们打算利用这些等位基因来开发高通量发现治疗药物的分析方法，使用患者细胞和/或来自我们小鼠的小鼠胚胎干细胞。

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.