权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Genetic and Functional Studies of Human Ciliary Syndromes

人类睫状体综合征的遗传和功能研究

基本信息

批准号：
10017953
负责人：
Erica Ellen Davis
金额：
$ 44.12万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
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：
2019-09-14 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017953
关键词：
3&apos Untranslated Regions Ablation Affinity Alleles Arts Bardet-Biedl Syndrome Benign Binding Binding Sites Biochemical Biological Candidate Disease Gene Cell physiology Cells Cilia Clinical Code Complement Custom DNA Sequence Rearrangement Data Data Set Defect Development Diagnostic Disease Dissection Embryo Etiology Exhibits Family Functional disorder Genes Genetic Genetic Complementation Test Genetic Diseases Genetic Epistasis Genetic Variation Genotype Harvest Human Human Genetics In Vitro Incidence Kidney Knowledge Larva Length Libraries Link Measurement Measures Meckel-Gruber syndrome Mediating MicroRNAs Missense Mutation Modality Modeling Modification Molecular Mutate Mutation Organ Pathogenicity Pathway interactions Patients Phenotype Protein Isoforms Proteins RNA Splicing Refractory Regulation Reporter Reporting Retina Role Severities Severity of illness Signal Transduction Site Small Interfering RNA Specificity Structure Syndrome Testing Therapeutic Tissue-Specific Splicing Tissues Transcript Variant WNT Signaling Pathway Work Zebrafish base causal variant ciliopathy cilium biogenesis cohort design differential expression dosage exome sequencing experimental study gene discovery genetic architecture genome sequencing genome wide screen genome-wide improved in vivo kinetosome novel overexpression pleiotropism preference protein function socioeconomics tool transcriptome transcriptomics whole genome

项目摘要

The ciliopathies are a group of >100 genetic disorders unified by overlapping structural and/or functional defects of the cilium and the basal body. The study of these disorders has highlighted fundamental developmental and homeostatic mechanisms, while offering the opportunity to develop computational and functional tools to discover new causal genes; to expand the phenotypic spectrum of known genes; and to design rational therapeutic paradigms. In the backdrop of striking progress during the past two decades, major challenges and opportunities remain. Specifically, despite a diagnostic rate that for some ciliopathies approaches 90%, the predictive power of the genotype at the primary recessive locus remains insufficient to inform clinical manifestation. This is in part because our understanding of the pathomechanisms of pleiotropy and variable expressivity remain poorly understood. Moreover, almost all ciliopathy discovery work to date has: (a) focused on coding mutations and genomic rearrangements; and (b) assumed that the pathogenicity of alleles is constant in all cellular contexts. In this Renewal, we aspire to improve upon these knowledge gaps. First, we will take advantage of a genome-wide siRNA screen on cells ablated for BBS4 that report on aberrant Wnt signaling. This experiment harvested 81 genes that, when suppressed, exacerbate ciliary cellular phenotypes and therefore represent de facto candidates for harboring either causal or epistatic mutations in patients with ciliary disease. We will test this hypothesis by sequencing our phenotypically diverse patient cohort and testing functionally resultant candidate genes and alleles using state-of-the-art in vivo tools. Critically, the majority of these 81 genes are not components of the ciliary apparatus, offering the opportunity to forge new biological links between ciliary dysfunction and other cellular processes. In parallel, we will pursue studies that will explore a new phenomenon of allele pathogenicity, in which bona fide pathogenic missense variants behave as deleterious to protein function in some splice isoforms but benign in others. Using a combination of in vivo complementation testing and in vitro biochemical studies, we will ask how common these phenomena are and whether subcellular localization or stability might represent informative biochemical drivers of these phenomena. Finally, through a genome-wide screen for miRNAs that regulate ciliogenesis, we discovered let-7b as a regulator of ciliary length. Subsequent transcriptomic analysis identified 42 ciliary genes with differential expression correlated to let-7b dosage, and which harbor predicted let-7b sites in their 3’ UTR. We will use this rich dataset to ask whether such miRNA binding sites in 3’ UTRs of known ciliopathy genes contribute to causality and modification in this group of disorders. Together, our studies will inform the genetic architecture of the ciliopathy disease entity by discovering sites that likely modulate the expressivity of disease; by exploring the context-dependent effect of pathogenic variation; and by interrogating the contribution to disease of a largely unexplored class of variants impacting regulatory mechanisms.

纤毛病是一组由结构和/或功能重叠而统一的遗传疾病