Moleclar Pathogenesis of Retinitis Pigmentosa Type 3

3 型色素性视网膜炎的分子发病机制

• 批准号: 6384172
• 负责人: PAULO A FERREIRA
• 金额: $ 33.1万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6384172
• 关键词: animal tissue; electron microscopy; fluorescence microscopy; gene expression; gene mutation; genetic library; genetic screening; guanosinetriphosphatase activating protein; human tissue; immunocytochemistry; immunoprecipitation; mass spectrometry; molecular pathology; northern blottings; nucleic acid sequence; pathologic process; polymerase chain reaction; protein isoforms; protein protein interaction; protein structure function; retinitis pigmentosa; rod cell; sex linked trait; visual photoreceptor; western blottings; yeast two hybrid system

DESCRIPTION (provided by applicant): Retinitis pigmentosa (RP) is a genetically and clinically heterogeneous retinal disease leading to photoreceptor cell death and ultimately, complete blindness. Yet, the molecular pathogenesis of most forms of inherited retinal degeneration remains until this date elusive. X-linked retinitis pigmentosa (XIRP) accounts for up to 33 percent of all forms of RP. The X-linked disorder, retinitis pigmentosa type 3, is responsible for about 75 percent of X-linked RP, 11 percent of all RP forms and it is considered to be the most severe form of RP. Recently, the genetic lesions leading to RP3 have been molecularly defined. They are caused by mutations in the so-called retinitis pigmentosa GTPase regulator (RPGR) gene in light of its homology to RCC1, a nucleotide-exchange factor for RanGTPase. All RP3-missense mutations to date identified are located in the RCC1-homologous domain. This gene is ubiquitously expressed but mutations in RPGR lead only to a visual phenotype primarily restricted to the retina. We have identified several retinal RPGR-interacting protein isoforms derived from the same gene that interact with RPGR in vitro and in vivo and these interactions are abrogated by human RP3-disease associated missense mutations. RPGR and its novel retinal substrate isoform(s) colocalize in the outer segments of rod photoreceptors. Thus, the novel RPGR substrates were designated RPGR interacting proteins (RPGRIPs). Also, the human RPGRIP gene colocalizes with RP16 locus. RPGRIPs contain very long, variable coiled-coil domains with homology to proteins involved in vesicular trafficking and a conserved, globular and C-terminal RPGR-interacting domain, suggesting that these proteins mediate vesicular-transport associated processes. The goals of this proposal are to understand the molecular pathogenesis of XIRP3, in particular, the molecular basis of the retina specific effects of RPGR mutations leading to RP3 and the biological role of the novel RPGRIPs.

描述（由申请人提供）： 色素性视网膜炎 (RP) 是一种遗传和临床异质性视网膜疾病 导致感光细胞死亡并最终完全失明的疾病。 然而，大多数遗传性视网膜变性的分子发病机制 直到今天仍然难以捉摸。 X 连锁色素性视网膜炎 (XIRP) 账户 占所有形式 RP 的比例高达 33%。 X连锁疾病，视网膜炎 3 型色素变性，约占 X 连锁 RP 的 75%，11 占所有 RP 形式的百分比，它被认为是 RP 最严重的形式。 最近，导致 RP3 的基因损伤已得到分子定义。 它们是由所谓的视网膜色素变性 GTP 酶突变引起的 鉴于其与 RCC1（一种核苷酸交换）的同源性，调节器（RPGR）基因 RanGTPase 的因子。迄今为止发现的所有 RP3 错义突变均位于 在 RCC1 同源域中。该基因普遍表达，但 RPGR 的突变仅导致视觉表型主要局限于 视网膜。我们已经鉴定了几种视网膜 RPGR 相互作用蛋白亚型 源自在体外和体内与 RPGR 相互作用的相同基因，并且 这些相互作用被人类 RP3 疾病相关错义消除 突变。 RPGR 及其新型视网膜底物亚型共定位于 视杆感光器的外节。因此，新型RPGR底物是 指定的 RPGR 相互作用蛋白 (RPGRIP)。此外，人类 RPGRIP 基因 与 RP16 基因座共定位。 RPGRIP 包含很长的可变线圈 与参与囊泡运输的蛋白质具有同源性的结构域和 保守的球状 C 端 RPGR 相互作用结构域，表明 这些蛋白质介导囊泡运输相关过程。的目标 该提案旨在了解 XIRP3 的分子发病机制， 特别是 RPGR 视网膜特异性作用的分子基础 导致 RP3 的突变以及新型 RPGRIP 的生物学作用。