Stargardt disease with low lipofuscin

常染色体隐性遗传性黄斑营养不良由ABCA4基因、STGD1、CRD、RP、 等等，都是孟德尔遗传导致儿童和成人视力丧失的最常见原因。 重要的是，5%(1：20)的普通人群携带与疾病相关的ABCA4等位基因，尽管不是全部 变种的组合是完全穿透的。尽管存在广泛的遗传变异，但有几个突变可以解释 疾病的大部分，往往会导致特定的、可辨别的亚型。最频繁的 疾病相关的ABCA4等位基因p.G1961E在20%到50%的患者中是一种原因突变 不同种族的人群。当以复合杂合子或纯合子状态存在时，它会导致 在一个非常一致的表型中，特征是早期中心凹视锥消融，但其他方面进展缓慢 以及ABCA4蛋白功能障碍的主要后果脂褐素的缺失或适度表达 积累。最近发现的另一种常见疾病的等位基因p.N1868I在普通人群中的存在比例为7% 它代表了一种“极端”的亚型等位基因，只有当反式与 有害等位基因。携带P.N1968I的患者也没有表现出明显的脂褐素积聚，慢性病 病情进展和疾病变化与P.G1961E相似。然而，与P.G1961E患者相比，P.N1868I是 与“保留中心凹”表型高度相关，即在黄斑病变过程中保留中心凹视锥 这种疾病。由于脂褐素积聚和随之而来的RPE毒性是 ABCA4病，现有数据表明，这种干预措施可能不适用于 P.G1961E和P.N1861I为因果变异。阐明这两个变体的功能后果 将指导多达一半患有ABCA4疾病的受影响个人的治疗选择。 拟议的研究战略利用互补的临床和功能方法学，并是 被组织成两个特定的目标。在第一个目标中，我们建议使用我们现有的基因和临床数据库， 积累的知识，以及先进的成像方法和功能测试的组合，以确定 亚型等位基因患者与其他有害等位基因患者之间精确的、可量化的差异。在 第二个目的是确定ABCA4亚型突变对蛋白质的功能影响 通过一系列研究确定突变蛋白的结构、定位、运输和 在IPSC来源的患者细胞培养和小鼠模型中，ATPase活性。这些研究的结果将 在疾病诊断和预后方面提供实质性帮助，并将作为设计临床试验的平台 ABCA4病的重要组成部分。

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.