Identifying the RNA Splicing and Gene Expression Changes that cause Congenital Myotonic Dystrophy

识别导致先天性强直性肌营养不良的 RNA 剪接和基因表达变化

• 批准号: 10402925
• 负责人: Nicholas Elwood Johnson
• 金额: $ 49.71万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-19 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402925
• 关键词: Adult; Age; Alternative Splicing; Behavioral; Biological; Biological Markers; Biopsy; Birth; Breathing; Cataract; Cell model; Child; Childhood; Clinical; Cognition; Congenital Myotonic Dystrophy; Cross-Sectional Studies; Data; Development; Disabled Children; Disease; Distal; Dose; Enrollment; Event; Fatigue; Fine needle aspiration biopsy; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Goals; Hereditary Disease; Individual; Intellectual impairment; Life; Link; Measures; Molecular; Motor; Muscle; Muscle Development; Muscle function; Muscle hypotonia; Muscle relaxation phase; Muscular Dystrophies; Myotonia; Myotonic Dystrophy; Myotonic dystrophy type 1; Natural History; Neuropsychology; Parents; Participant; Pathogenesis; Pathogenicity; Pathology; Pattern; Phase; Phenotype; Physical Function; Population; Problem behavior; Proteins; Published Comment; RNA; RNA Splicing; Research; Research Personnel; Respiratory Insufficiency; Risk; Role; Sampling; Symptoms; Testing; Therapeutic Trials; Transcript; Variant; Visit; Work; autistic; biobank; biomarker development; clinical outcome measures; clinical phenotype; clinical predictors; clinically relevant; cohort; design; drug development; early onset; expectation; experimental study; feeding; functional outcomes; gastrointestinal symptom; induced pluripotent stem cell; molecular marker; mortality; new therapeutic target; novel; public health relevance; research clinical testing; specific biomarkers; therapeutic development; therapeutic target; therapy development; transmission process

Abstract Congenital myotonic dystrophy, the most severe form of myotonic dystrophy, causes weakness, breathing problems, and feeding problems at birth. During childhood, children often have intellectual impairment, fatigue, behavioral concerns and weakness. Importantly, many of the symptoms are distinct from those adults with myotonic dystrophy. In adults with myotonic dystrophy, a toxic RNA repeat expansion leads to global misregulation of RNA splicing. It is not clear if the same mechanism is involved in congenital myotonic dystrophy. Such information is critical since new treatments for myotonic dystrophy target this issue. This proposal is designed to evaluate the pathogenesis of congenital myotonic dystrophy. The investigators will evaluate changes in RNA splicing and gene expression in muscle samples and then validate these changes in a DM1 cell model by enrolling 100 children below the age of 15 with congenital myotonic dystrophy. Children will be evaluated with measures of physical function and cognition at the baseline visit and a fine needle aspirate of the muscle will be collected. Children with congenital myotonic dystrophy will return for a clinical evaluation at 12 months. These children will be compared to 30 histopathologically normal muscle biopsies. In Aim 1, we will initially evaluate changes in RNA splicing and correlate these with the clinical outcome measures to identify those specific transcripts that most directly correlate with symptoms. Key RNA splicing events will be evaluated as predictors of clinical function at the 12-month visit. In Aim 2, we will also evaluate secondary gene expression changes in a similar manner, which has not been done in myotonic dystrophy. Once key gene expression and RNA splicing signatures have been identified, Aim 3 will evaluate them in a DM1 cell model to assess the role of MBNL1 sequestration and other splicing regulators for a particular splice event. This is a key pathogenic mechanism in DM1. At the completion of this project, we will have identified key biomarkers and performed preliminary experiments to understand the role of these events in the mechanism of disease. By better understanding the pathogenesis of congenital myotonic dystrophy, we allow these children access to disease modifying therapies in myotonic dystrophy, as well as identify new therapeutic targets for drug development.

抽象的 先天性肌发育症，是最严重的肌营养不良形式，导致 出生时的弱点，呼吸问题和进食问题。在童年时期，孩子经常 有智力障碍，疲劳，行为问题和弱点。重要的是，很多 症状与那些患有肌发育症的成年人不同。在成年人中 营养不良，有毒的RNA重复膨胀会导致RNA剪接的整体上调。它不是 清楚地清楚先天肌营养不良症是否涉及相同的机制。这样的信息是 至关重要的，因为新的肌营养不良症的新疗法针对这个问题。该建议的设计 评估先天性肌发育症的发病机理。调查人员将评估 RNA剪接和肌肉样品中基因表达的变化，然后验证这些 通过招募15岁以下的15岁儿童，先天性的100名儿童通过招募DM1细胞模型的变化 肌发育症。将通过身体机能和 将收集基线访问的认知和肌肉的细针抽吸。孩子们 先天性肌病性营养不良症将在12个月时返回进行临床评估。这些 将将儿童与30个组织病理学正常的肌肉活检进行比较。 在AIM 1中，我们最初将评估RNA剪接的变化，并将其与 临床结果指标，以识别与与 症状。关键的RNA剪接事件将被评估为在 12个月的访问。在AIM 2中，我们还将评估相似的次级基因表达变化 方式，尚未在肌发育症中进行。一旦关键基因表达和RNA 已经确定了剪接特征，AIM 3将在DM1细胞模型中评估它们以评估 MBNL1隔离和其他剪接调节剂在特定剪接事件中的作用。这 是DM1中的关键致病机制。该项目完成时，我们将确定 关键的生物标志物并进行了初步实验，以了解这些事件的作用 在疾病机理中。通过更好地理解先天性肌病的发病机理 营养不良，我们允许这些儿童进入肌动子中的疾病修饰疗法 营养不良，并确定用于药物开发的新治疗靶标。

项目成果

Evaluation of effects of continued corticosteroid treatment on cardiac and pulmonary function in non-ambulatory males with Duchenne muscular dystrophy from MD STARnet.

• DOI: 10.1002/mus.27490
• 发表时间: 2022-07
• 期刊: Muscle & nerve
• 影响因子: 3.4

High throughput screening for expanded CTG repeats in myotonic dystrophy type 1 using melt curve analysis.

• DOI: 10.1002/mgg3.1619
• 发表时间: 2021-04
• 期刊: Molecular genetics & genomic medicine
• 影响因子: 2
• 作者: Butterfield RJ;Imburgia C;Mayne K;Newcomb T;Dunn DM;Duval B;Feldkamp ML;Johnson NE;Weiss RB
• 通讯作者: Weiss RB

Lean tissue mass measurements by dual-energy X-ray absorptiometry and associations with strength and functional outcome measures in facioscapulohumeral muscular dystrophy.

通过双能 X 射线吸收测定法测量瘦肉组织质量，以及与面肩肱型肌营养不良症的力量和功能结果测量的关联。

• DOI: 10.1016/j.nmd.2023.06.008
• 发表时间: 2023
• 期刊: Neuromuscular disorders : NMD
• 作者: Wang,LeoH;Leung,DorisG;Wagner,KathrynR;Lowry,SarahJ;McDermott,MichaelP;Eichinger,Katy;Higgs,Kiley;Walker,Michaela;Lewis,Leann;Martens,WilliamB;Mul,Karlien;Sansone,ValeriaA;Shieh,Perry;Elsheikh,Bakri;LoRusso,Samantha;Bu
• 通讯作者: Bu

12-Month progression of motor and functional outcomes in congenital myotonic dystrophy.

• DOI: 10.1002/mus.27147
• 发表时间: 2021-03
• 期刊: Muscle & nerve
• 影响因子: 3.4
• 作者: Quigg KH;Berggren KN;McIntyre M;Bates K;Salmin F;Casiraghi JL;DʼAmico A;Astrea G;Ricci F;McKay MJ;Baldwin JN;Burns J;Campbell C;Sansone VA;Johnson NE
• 通讯作者: Johnson NE

Association of genetic mutations and loss of ambulation in childhood-onset dystrophinopathy.

• DOI: 10.1002/mus.27113
• 发表时间: 2021-03
• 期刊: Muscle & nerve
• 影响因子: 3.4
• 作者: Haber G;Conway KM;Paramsothy P;Roy A;Rogers H;Ling X;Kozauer N;Street N;Romitti PA;Fox DJ;Phan HC;Matthews D;Ciafaloni E;Oleszek J;James KA;Galindo M;Whitehead N;Johnson N;Butterfield RJ;Pandya S;Venkatesh S;Bhattaram VA
• 通讯作者: Bhattaram VA