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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.

摘要

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