Stargardt disease with low lipofuscin

脂褐质低的 Stargardt 病

• 批准号: 10361403
• 负责人: RANDO L ALLIKMETS
• 金额: $ 50.85万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10361403
• 关键词: 220kDa rod outer segment rim protein; ATP phosphohydrolase; Ablation; Adult; Affect; Alleles; Atrophic; Blindness; Cell Culture Techniques; Cells; Characteristics; Child; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Collection; Cone; Correlation Studies; Counseling; Coupled; Cryoelectron Microscopy; Data; Diagnosis; Diagnostic; Disease; Disease Progression; Disease model; Exhibits; Flecks; Frequencies; Functional disorder; Future; General Population; Genes; Genetic; Genetic Databases; Genetic Screening; Genetic Variation; Genotype; Human Genetics; Individual; Inherited; Intervention; Knock-in Mouse; Knowledge; Link; Lipofuscin; Methodology; Molecular; Molecular Structure; Mus; Mutation; Natural History; Outcome Study; Patient Care; Patients; Penetrance; Persons; Phenotype; Photoreceptors; Population; Prognosis; Research; Retina; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Stargardt' s disease; Structure; Subgroup; Testing; Therapeutic; Toxic effect; United States; Variant; Vertebrate Photoreceptors; base; causal variant; cell type; clinical database; clinical heterogeneity; clinical imaging; clinical phenotype; cohort; cone-rod dystrophy; design; diagnostic accuracy; disease diagnosis; disease heterogeneity; disease phenotype; disorder subtype; genetic analysis; imaging modality; improved; individualized medicine; induced pluripotent stem cell; insight; macula; macular dystrophy; morphogens; mouse genetics; mouse model; mutant; next generation; patient screening; preservation; prognostic; programs; protein function; protein structure; targeted treatment; therapeutic target; translational study

Autosomal recessive macular dystrophies caused by mutations in the ABCA4 gene, STGD1, CRD, RP, etc., are together the most prevalent Mendelian inherited cause of vision loss in both children and adults. Importantly, 5% (1:20) of the general population carry a disease-associated ABCA4 allele although not all combinations of variants are fully penetrant. Despite extensive genetic variability, several mutations account for large fractions of the disease and often result in specific, discernable sub-phenotypes. The most frequent disease-associated ABCA4 allele, p.G1961E, is a causal mutation in 20% to 50% of patients amongst ethnically different populations. When present in either compound heterozygous or homozygous state it results in a very consistent phenotype characterized by early ablation of foveal cones, but otherwise slow progression and the absence or moderate expression of the major consequence of ABCA4 protein dysfunction, lipofuscin accumulation. Another recently identified common disease allele, p.N1868I, is present in ~7% in the general population and represents an ‘extremely’ hypomorphic allele, which is causal only when in trans with a deleterious allele. Patients harboring p.N1968I also exhibit no significant lipofuscin accumulation, slow disease progression and disease changes similar to p.G1961E. However, in contrast to p.G1961E patients, p.N1868I is highly associated with the “foveal sparing” phenotype, i.e., preservation of foveal cones during the course of the disease. Since lipofuscin accumulation, and consequent RPE toxicity, is the common therapeutic target for ABCA4 disease, existing data suggest that such interventions may have no applicability for patients harboring p.G1961E and p.N1861I as causal variants. Elucidating the functional consequences of these two variants would direct treatment options for up to half of affected individuals with ABCA4 disease. The proposed research strategy utilizes complementary clinical and functional methodology and is organized into two Specific Aims. In the first Aim, we propose using our existing genetic and clinical databases, accumulated knowledge, and a combination of advanced imaging methods and functional testing to determine precise, quantifiable differences between patients with hypomorphic alleles and other deleterious alleles. In the second Aim we will determine the functional consequences of the hypomorphic ABCA4 mutations on protein function by a combination of studies, which determine the mutant protein structure, localization, transport and ATPase activity, in iPSC-derived patient cell cultures and mouse models. The outcome of these studies will substantially aid in disease diagnosis, prognosis and will serve as a platform for designing clinical trials for a significant fraction of ABCA4 disease.

由ABCA 4基因、STGD 1、CRD、RP突变引起的常染色体隐性黄斑营养不良， 等等，是儿童和成人视力丧失的最普遍的孟德尔遗传原因。 重要的是，5%（1：20）的普通人群携带疾病相关的ABCA 4等位基因，尽管不是所有人都携带。 变体的组合是完全渗透的。尽管存在广泛的遗传变异，但几种突变导致了 疾病的大部分，并经常导致特定的，可辨别的亚表型。最常见的 疾病相关的ABCA4等位基因p.G1961E是20%至50%的患者中的致病突变， 不同种族的人。当以复合杂合或纯合状态存在时， 在一个非常一致的表型中，特征在于中央凹锥体的早期消融，但在其他方面进展缓慢 以及ABCA 4蛋白功能障碍的主要后果脂褐素的缺乏或中度表达 积累另一个最近发现的常见疾病等位基因，p.N1868I，在一般人群中存在约7%。 人口和代表一个'极端'亚型等位基因，这是因果关系，只有当在反式与一个 有害等位基因携带p.N1968I的患者也没有表现出显著的脂褐素积累， 进展和疾病变化与p.G1961E相似。然而，与p.G1961E患者相比，p.N1868I是 与“中央凹保留”表型高度相关，即，视网膜中央凹锥体的保存 这种疾病由于脂褐素积累和随之发生的RPE毒性是视网膜色素变性的常见治疗靶点， ABCA4疾病，现有数据表明，这种干预措施可能不适用于患有ABCA4疾病的患者。 p.G1961E和p.N1861I作为致病变体。阐明这两种变体的功能后果 将为多达一半的ABCA4疾病患者提供治疗选择。 拟议的研究策略利用互补的临床和功能方法， 分为两个具体目标。在第一个目标中，我们建议使用我们现有的遗传和临床数据库， 积累的知识，并结合先进的成像方法和功能测试，以确定 具有亚多态等位基因和其他有害等位基因的患者之间存在精确、可量化的差异。在 第二个目的是确定亚纯型ABCA 4突变对蛋白质的功能影响， 功能的组合研究，确定突变蛋白质的结构，定位，运输和 ATP酶活性，在iPSC衍生的患者细胞培养物和小鼠模型中。这些研究的结果将 大大有助于疾病诊断、预后，并将作为设计临床试验的平台， ABCA4疾病的重要部分。