Identification of Genetic and Molecular Pathways in Congenital Rare Disorders Affecting the Brain and Muscle

影响大脑和肌肉的先天性罕见疾病的遗传和分子途径的鉴定

基本信息

批准号：
10671469
负责人：
M. CHIARA MANZINI
金额：
$ 32.87万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10671469
关键词：
Affect Biochemical Biopsy Brain Childhood Code Cognitive deficits Cohort Studies Complex Consumption DNA Sequence Alteration DNA sequencing Development Developmental Delay Disorders Disease Dystroglycan Embryo Extracellular Matrix Eye Family Future Genes Genetic Genetic Heterogeneity Genetic Models Genetic study Genome Genotype Goals Histologic Human Individual Modeling Molecular Motor Muscle Muscle Cells Muscle Development Muscular Dystrophies Mutate Mutation Neurons Nucleic Acid Regulatory Sequences Organ Pathogenesis Pathway interactions Phenotype Postdoctoral Fellow Protein Glycosylation RNA Splicing Rare Diseases Research Research Personnel Severities Specificity Testing Therapeutic Therapeutic Intervention Therapy Evaluation Time Translations Untranslated RNA Variant Work Zebrafish analysis pipeline bioinformatics pipeline clinical heterogeneity cognitive disability cohort congenital muscular dystrophy cost data integration deafness disease-causing mutation dystroglycanopathy exome gene discovery genetic analysis genetic architecture genetic disorder diagnosis genetic testing genome sequencing glycosylation glycosyltransferase in vivo Model mortality mouse model next generation sequencing novel novel therapeutics overexpression patient population targeted treatment therapeutic evaluation therapy development transcriptome transcriptome sequencing treatment group whole genome

项目摘要

ABSTRACT Congenital muscular dystrophies (CMDs) are a group of heterogeneous pediatric disorders leading to motor and developmental delay, and childhood mortality. CMDs have variable presentation often affecting multiple organs, such as the eyes and brain. While this clinical heterogeneity initially hindered genetic analyses, the ad- vent of next-generation sequencing and whole exome studies greatly increased gene identification reaching up to 30 genes, with eight genes identified in 2012-2013, three of which by the PI. Each new gene has provided a different piece of a complex puzzle, not only providing a genetic diagnosis for the affected individuals, but also informing us on how the mutated genes converge onto shared molecular pathways such as protein glycosyla- tion. Yet, our group and others have found that mutations in each gene are only present in a small portion of cases, and 30-40% of cases remain unexplained. In parallel, the large number of known genes has hindered therapy development as it remains unclear how cases with different genotypes and phenotypes can be grouped for treatment. The PI has focused the past decade on studying the genetics of CMD and developing zebrafish models to define how disease-causing mutations affect muscle and brain development. Through these studies, we have devel- oped our central hypotheses that most CMD genes regulate interactions with the extracellular matrix (ECM) through glycosylation, and that unexplained cases will either carry mutations in novel genes involved in cell- ECM interaction or noncoding variants in already known CMD genes. The proposed studies will test these hypotheses through two independent and complementary Specific Aims. Specific Aim 1 will leverage the multi- ple zebrafish models we have developed for known CMD genes to test whether increasing glycosylation will restore cell-ECM interactions in the muscle and brain in different genetic models of CMD. We will 1) define which biochemical deficits are shared by different genetic mutations in muscle cells and neurons, and 2) test whether changes in glycosylation can be beneficial in different forms of CMD. This workflow can then be ex- panded to future therapeutic interventions and novel disease genes can be rapidly taken from gene identifica- tion to therapy evaluation. Specific Aim 2 will close the gap in gene discovery in CMDs by testing the hypothe- sis that undiagnosed CMD cases are caused by a combination of rare mutations in novel genes and non- coding mutations in intronic/regulatory regions of known CMD genes. We have developed a next generation sequencing and bioinformatic pipeline that will integrate data from exome, genome, and transcriptome to iden- tify coding, splicing, and regulatory variants to fully unravel the genetics of CMD. These studies will directly impact the CMD fields by both discovering how different disease genes contribute to pathogenesis and by developing novel genetic tests for the global patient population.

抽象的先天性肌肉营养不良（CMD）是一组异质的小儿疾病，导致运动和发育延迟和儿童死亡率。 CMD具有可变呈现通常会影响多重器官，例如眼睛和大脑。尽管这种临床异质性最初阻碍了遗传分析，但下一代测序和整个外显子组研究大大增加了基因鉴定到30个基因，在2012 - 2013年鉴定出八个基因，其中三个由PI鉴定。每个新基因都提供了复杂的难题的不同部分，不仅为受影响的个体提供遗传诊断，而且还提供告知我们突变基因如何融合到共同的分子途径上，例如蛋白质糖基 - tion。然而，我们的小组和其他人发现，每个基因中的突变仅存在于一小部分病例和30-40％的病例仍无法解释。同时，大量已知基因已阻碍尚不清楚如何将具有不同基因型和表型的病例分组用于治疗。 PI在过去十年中的重点是研究CMD的遗传学并开发斑马鱼模型以定义引起疾病的突变如何影响肌肉和大脑发育。通过这些研究，我们有了Devel- 选择了我们的中心假设，即大多数CMD基因都调节了与细胞外基质（ECM）的相互作用通过糖基化，无法解释的病例要么在与细胞的新基因中携带突变 ECM相互作用或已知CMD基因中的非编码变体。拟议的研究将测试这些通过两个独立和互补的特定目标提出假设。特定目标1将利用多我们为已知CMD基因开发的斑马鱼模型，以测试增加糖基化是否会在CMD的不同遗传模型中恢复肌肉和大脑中的细胞ECM相互作用。我们将1）定义肌肉细胞和神经元中不同的遗传突变共享哪些生化缺陷，以及2）测试糖基化的变化是否在不同形式的CMD中是有益的。然后可以将此工作流程可以迅速从基因鉴定中迅速采取治疗干预措施和新型疾病基因治疗评估。特定的目标2将通过测试假设来缩小CMD中基因发现的差距 SIS未诊断的CMD病例是由新基因和非稀有突变组合的组合引起的已知CMD基因的内含子/调节区域中的编码突变。我们已经开发了下一代测序和生物信息学管道将将外显子，基因组和转录组的数据整合到iden- 介绍编码，剪接和调节变体，以完全揭示CMD的遗传学。这些研究将通过发现不同疾病基因如何促进CMD领域的直接影响CMD领域发病机理并通过为全球患者人群开发新的基因检测。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Novel mutation identification and copy number variant detection via exome sequencing in congenital muscular dystrophy.

DOI：
10.1002/mgg3.1387
发表时间：
2020-11
期刊：
Molecular genetics & genomic medicine
影响因子：
2
作者：
Cauley ES;Pittman A;Mummidivarpu S;Karimiani EG;Martinez S;Moroni I;Boostani R;Podini D;Mora M;Jamshidi Y;Hoffman EP;Manzini MC
通讯作者：
Manzini MC