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: 6635679
• 负责人: PAULO A FERREIRA
• 金额: $ 30万
• 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/6635679
• 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）是一种遗传和临床上异质性的视网膜 导致感光细胞死亡的疾病，并最终完全失明。 然而，大多数形式的遗传性视网膜变性的分子发病机理 直到这个日期一直难以捉摸。 X连锁视网膜炎色素（XIRP）帐户 最多33％的RP。 X连锁疾病，视网膜炎 色素3型，约有75％的X连锁RP，11 在所有RP形式中，它被认为是最严重的RP形式。 最近，已经定义了导致RP3的遗传病变。 它们是由所谓的视网膜炎GTPase中突变引起的 根据其与RCC1的同源性，调节剂（RPGR）基因是核苷酸 - 交换 rangtpase的因素。迄今已确定的所有RP3无数突变均位于 在RCC1同源域中。该基因无处不在，但 RPGR中的突变仅导致视觉表型，主要限于 视网膜。我们已经确定了几个视网膜RPGR相互作用的同工型 来自与RPGR在体外和体内与RPGR相互作用的基因 这些相互作用被人类rp3-疾病相关的失误所消除 突变。 RPGR及其新型的视网膜底物同工型（S）共定位 杆感光体的外部段。因此，新型的RPGR底物是 指定的RPGR相互作用蛋白（RPGRIP）。另外，人类rpgrip基因 与RP16基因座共定位。 RPGRIP包含很长的，可变的盘绕线圈 与参与囊泡贩运的蛋白质同源的域和 保守的，球状和C末端的RPGR相互作用域，表明 这些蛋白质介导了囊泡交通相关的过程。目标 该建议是了解xirp3的分子发病机理 特别是RPGR的视网膜特异性效应的分子基础 突变导致RP3和新型RPGRIP的生物学作用。