MOLECULAR BASIS OF SYNDROMIC RETINITIS PIGMENTOSA

这个项目的目的是克隆和鉴定一种形式的基因。 综合症视网膜色素变性(RP)，称为。哈勒沃登-斯帕茨 综合征(HSS)，以视网膜电图、脂褐素异常为特征 视网膜色素上皮中的堆积和色素 视网膜病变。其他特征包括由于大量的铁引起的肌张力障碍。 基底节积聚，进行性恶化导致 导致早逝。尽管脂质过氧化是一种假想的机制 导致HSS表型，不存在关于分子或 高血压病患者存在生化缺陷。我们有一个独特的机会来绘制HSS 基因连锁分析(纯合性定位)在一个血缘关系中的应用 有多名受影响成员的阿米什家庭。一旦HSS基因被 映射后，我们将搜索候选基因的突变，以及 鉴定可能含有HSS基因的新转录序列。我们 然后将通过同源性来表征该基因及其蛋白质产物 对已知序列的研究。了解这一现象的分子基础 疾病将导致对病理生理的更好的理解。 导致其多效性的过程。 了解一种罕见疾病的病因学通常会启发 发病机制常见于常见、相关疾病。此外，通过研究 综合征RP，我们可以使用关于所有综合征的信息 表现(例如，组织表达模式、常见代谢或 发育途径)来对疾病机制进行理论分析。关于A的推论 缺陷基因的病理生理过程被证明是令人沮丧的 视网膜特异基因突变所导致的RP的形式。HSS计划 基因不是视网膜特有的，它的缺陷一定可以解释视杆细胞 光感受器变性以及局部脑铁蓄积。 一旦HSS基因被克隆和鉴定，另一种病理 变化可能为理解以下机制提供背景 色素性视网膜病变。由于这一非视网膜特异性过程中的缺陷 可能导致其他形式的综合征和孤立的RP，并可能在 脂褐素蓄积障碍，包括黄斑老化 退化，鉴定HSS基因可能会导致更大 对RP以及与SENE相关的黄斑营养不良的认识 安斯。 HSS项目构成了Hayflick博士培训的研究核心 成为一名独立的生物医学研究者。迈克尔·利特博士， 在国际公认的遗传学领域，他会是她的首要 理查德·韦勒伯博士的赞助商，在遗传病研究方面取得了成就 视网膜疾病，作为次要赞助商。她训练的独特长处 计划包括在访问调查员中进行一段时间的密集学习 通过国家人类基因组研究中心的计划，该中心将 为她提供将补充而不是重复现有的专业知识 大学的研究优势和俄勒冈健康科学大学 以及分子和医学遗传学研究环境系， 有效地促进了与不同的杰出群体的合作 调查人员。

The aim of this project is to clone and characterize the gene for a form of syndromic retinitis pigmentosa (RP), called. Hallervorden-Spatz syndrome (HSS) and characterized by abnormal electroretinogram, lipofuscin accumulation in the retinal pigment epithelium, and pigmentary retinopathy. Other features include dystonia, due to massive iron accumulation in the basal ganglia, and progressive deterioration leading to early death. Though lipid peroxidation is an hypothesized mechanism leading to the HSS phenotype, no knowledge exists of the molecular or biochemical defect in HSS. We have a unique opportunity to map the HSS gene using linkage analysis (homozygosity mapping) in a consanguineous Amish family with multiple affected members. Once the HSS gene has been mapped, we will search for mutations in candidate genes, as well as identify novel transcribed sequences that may contain the HSS gene. We will then characterize the gene and its protein product through homology studies to known sequences. Knowledge of the molecular basis of this disease will lead to a better understanding of the pathophysiologic process causing its pleiotropic effects. Understanding the etiology of a rare disease will often illuminate the mechanism at work in common, related diseases. Furthermore, by studying syndromic RP, we can use information about all of the syndrome manifestations (e.g. patterns of tissue expression, common metabolic or developmental pathways) to theorize a disease mechanism. Inference of a pathophysiologic process from a defective gene has proved frustrating for the forms of RP that are due to mutation in retina-specific genes. The HSS gene is not retina-specific, and a defect in it must account for rod photoreceptor degeneration as well as regional brain iron accumulation. Once the HSS gene is cloned and characterized, the other pathologic changes may provide a context for understanding the mechanism of pigmentary retinopathy. Since defects in this non-retina-specific process may cause other forms of syndromic and isolated RP and may be integral in disorders of lipofuscin accumulation, including aging macular degeneration, identification of the HSS gene may lead to greater understanding of RP as well as the macular dystrophies associated with sene ence. The HSS project forms the research core of Dr. Hayflick's training to become an independent biomedical investigator. Dr. Michael Litt, internationally recognized in the field of genetics, will he her primary sponsor with Dr. Richard Weleber, accomplished in the study of hereditary retinal diseases, as secondary sponsor. Unique strengths of her training program include a period of intense study in the Visiting Investigator Program through the National Center for Human Genome Research, which will provide her with expertise that will complement but not duplicate existing University research strengths, and the Oregon Health Sciences University and Department of Molecular and Medical Genetics research environments, which effectively foster collaboration with a diverse group of outstanding investigators.