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Integrated clinical, genetic and functional analysis of the ABCA4 locus

ABCA4 基因座的综合临床、遗传和功能分析

基本信息

批准号：
10382301
负责人：
RANDO L ALLIKMETS
金额：
$ 42.08万
依托单位：
COLUMBIA UNIVERSITY 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：
2019-06-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382301
关键词：
220kDa rod outer segment rim protein Address Affect Age Alleles Atrophic Biological Assay CRISPR/Cas technology Cell Culture Techniques Cell Line Clinical Clinical Data Clinical Treatment Clinical Trials Code Collection Consensus Sequence Counseling Coupled Data Defect Diagnosis Diagnostic Disease Enhancers Family Flecks Frequencies Future Gene Expression Genes Genetic Genetic Databases Genetic Screening Genetic Variation Genomics Genotype Goals Image Introns Knowledge Link Lipofuscin Medical Genetics Messenger RNA Methodology Methods Modality Mus Mutate Mutation Onset of illness Outcome Study Pathogenicity Patient Care Patients Pattern Penetrance Persons Phenotype Population Prognosis RNA RNA Splicing Rare Diseases Reporter Research Rest Retina Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Severities Site Spliced Genes Stargardt&apos s disease Statistical Data Interpretation Structure Subgroup Testing United States Untranslated RNA Variant base cell type clinical care clinical database clinical heterogeneity clinical phenotype clinical prognosis cohort combinatorial cone-rod dystrophy design diagnostic accuracy disease diagnosis disease heterogeneity disorder subtype genetic analysis genetic approach genetic testing genotyped patients improved in silico induced pluripotent stem cell insight molecular modeling mutant novel patient screening predictive modeling prognostic programs promoter segregation therapy design translational study

项目摘要

Mutations in the ABCA4 gene are responsible for a wide variety of retinal degeneration phenotypes, including Stargardt disease (STGD), cone-rod dystrophy (CRD) and retinitis pigmentosa (RP). Different combinations of >900 ABCA4 mutant alleles result in distinct phenotypes in a continuum of disease manifestations. Variation in the ABCA4 locus has emerged as the most prevalent cause of Mendelian retinal disease, with an estimated 1/20 people across all populations carrying a potential disease-associated variant in this gene. Genetic analyses of ABCA4-associated retinal disease have been substantially advanced in recent years. New methods, such as direct sequencing of the entire genomic ABCA4 locus, have allowed detecting up to 80% of the disease-associated ABCA4 alleles, including 2 (both) mutations in ~65-75% of patients. Of these 75% are in the coding region and 25% in introns, more than half of which are outside of splice consensus sequences. Of the rest, 1 mutation is detected in ~20% of patients while no disease-associated alleles are found in another 10% of screened patients with phenotypes compatible with the ABCA4 disease. These data suggest that many (rare) disease-associated ABCA4 alleles are yet to be identified and, most importantly, unequivocally confirmed by adequate functional analyses. We will test the hypothesis that a combination of advanced genetic screening coupled with advanced functional analyses of ABCA4 alleles from non-coding sequences is necessary to unequivocally determine the ABCA4-associated disease load. The proposed research program, based on large, comprehensively characterized familial cohort of ABCA4 disease, is using integrated approaches of genetic analyses, quantified clinical data and functional analyses to generate a predictive model for ABCA4 disease. The ultimate goal of the proposed project is to complete the analysis of the ABCA4 locus. The research program is organized into two Specific Aims. In the first Aim, we propose a novel combinatorial pipeline utilizing our existing clinical and genetic databases, accumulated knowledge, and advanced in silico methodology to predict most disease-associated variants in the coding and non-coding sequences of the entire ABCA4 locus. In the second Aim we will confirm or reject the variants in non-coding sequences for disease association by functional testing ABCA4 RNA from mutated iPSC lines for splicing and expression defects. The outcome of these studies will substantially aid in disease diagnosis, prognosis and will serve as a platform for selecting patients for emerging clinical trials geared to delay the onset, or arrest the progression, of ABCA4-associated diseases.

ABCA4基因的突变导致了多种视网膜变性表型，