Epigenetic dysregulation of muscle differentiation in Kabuki syndrome

歌舞伎综合征肌肉分化的表观遗传失调

• 批准号: 10560603
• 负责人: EMANUELA GUSSONI
• 金额: $ 53万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-02 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560603
• 关键词: ATAC-seq; Address; Adult; Affect; Automobile Driving; Cardiac; Cells; Clinical; Complex; Data; Defect; Development; Developmental Delay Disorders; EZH2 gene; Embryonic Development; Enhancers; Epigenetic Process; Etiology; Exhibits; Fiber; Functional disorder; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Heterogeneity; Heterozygote; Histones; Human; Impairment; Individual; Intellectual functioning disability; Kabuki Make-Up Syndrome; Kidney; Knowledge; Life; Link; Methyltransferase; Modeling; Molecular Target; Mus; Muscle; Muscle Fatigue; Muscle Fibers; Muscle function; Muscle hypotonia; Muscle satellite cell; Muscular Atrophy; Mutant Strains Mice; Mutate; Mutation; Myosin ATPase; Neural Conduction; Organ; Pathogenicity; Patient Care; Patients; Phenotype; Proteins; Rare Diseases; Repression; Role; Secondary to; Severities; Signal Transduction; Skeletal Muscle; Specific qualifier value; Symptoms; System; Tissues; Work; epigenomics; experimental study; gene network; hearing impairment; improved; loss of function; mouse model; muscle form; postnatal; promoter; protein complex; reduced muscle strength; satellite cell; stem cell differentiation; stem cell self renewal; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Kabuki Syndrome (KS) is a rare disease caused by heterozygous pathogenic mutations in two known genes: KDM6A (~20% cases) and KMT2D (~80% cases). Both genes are broadly expressed in many tissues and their activity spans temporally from development to postnatal adult life. KS patients present with various degrees of clinical abnormalities, including severe muscular hypotonia and reduced muscle strength. Whether hypotonia develops as a consequence of nerve conduction malfunction or it is due to a cell-autonomous primary defect in skeletal muscle is currently unknown. Further, skeletal muscle tissue from patients affected by KS has not been thoroughly studied. Our main hypothesis is that skeletal muscle tissue is primarily affected by mutations in KMT2D, which results in dysregulated muscle function. We propose to validate our hypothesis via the following specific Aims: 1) Define primary versus secondary muscle function defects using constitutive and conditional mouse models of KS; 2) Determine the gene networks and molecular targets of KMT2D driving muscle hypotonia in constitutive and conditional KS mouse models; 3) Define muscle satellite cell heterogeneity and `immaturity' in conditional and constitutive KS models, as well as in human patients. The work proposed will fill major gaps in our lack of knowledge about etiology of hypotonia in Kabuki syndrome and will pave the way for clinical improvements of patient care.

项目摘要 歌舞伎综合征（KS）是一种罕见的疾病，由两种已知的 基因：KDM 6A（约20%病例）和KMT 2D（约80%病例）。这两种基因在许多人中广泛表达， 组织和它们的活动在时间上跨越从发育到出生后的成年生活。KS患者存在 伴有不同程度的临床异常，包括严重的肌张力减退和肌肉萎缩 实力无论张力减退的发展是由于神经传导功能障碍，还是由于 骨骼肌中的细胞自主性原发性缺陷目前是未知的。此外，骨骼肌组织 尚未对KS患者进行彻底研究。我们的主要假设是骨骼肌 组织主要受到KMT 2D突变的影响，这导致肌肉功能失调。我们 我建议通过以下具体目标来验证我们的假设：1）定义主要与次要 使用KS的组成性和条件性小鼠模型的肌肉功能缺陷; 2）确定基因 在组成性和条件性KS中驱动肌肉张力减退的KMT 2D的网络和分子靶点 小鼠模型; 3）在条件性和组成性中定义肌肉卫星细胞异质性和“不成熟” KS模型，以及人类患者。所提出的工作将填补我们知识缺乏的主要空白 探讨歌舞伎综合征肌张力低下的病因，为临床改善患者的肌张力提供依据 在乎