Exploring Kabuki Syndrome as a Treatable Cause of Intellectual Disability

探索歌舞伎综合症作为智力障碍的可治疗原因

• 批准号: 8609254
• 负责人: Hans Tomas Bjornsson
• 金额: $ 40.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-21 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8609254
• 关键词: Alleles; Biochemical Markers; Biological Assay; Biological Markers; Cells; Child; Chromatin; Critical Pathways; Data; Defect; Development; Diagnosis; Disease; Disease Clusterings; Excision; Fluorescence; Fluorescence-Activated Cell Sorting; Gene Expression; Gene Family; Heterozygote; Hippocampus (Brain); Histone Acetylation; Histone Deacetylase Inhibitor; Histones; Intellectual functioning disability; Intervention; Kabuki Make-Up Syndrome; Life; Lymphocyte; Memory; Modeling; Monitor; Mus; Neurons; Pathogenesis; Patients; Pharmaceutical Preparations; Pilot Projects; Proteins; Reporter; Rubinstein-Taybi Syndrome; School-Age Population; Severities; Subgroup; Syndrome; System; Testing; Tetracyclines; Therapeutic Agents; Therapeutic Effect; Time; Tissues; Transgenic Mice; Treatment Protocols; Work; base; cell type; embryonic stem cell; epigenome; gene function; high throughput screening; histone modification; improved; in vitro activity; in vivo; insight; mouse model; neurogenesis; new therapeutic target; postnatal; public health relevance; research study; response; screening; therapy development

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.

描述（由申请人提供）：智力残疾在美国很常见（占学龄儿童的2%）。尽管如此，几乎没有治疗方案可用于这一异质性疾病组。在某种程度上，智力残疾无法治愈的普遍观念阻碍了治疗的发展。但是，如果能找到一个子群