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）： 视网膜色素变性（RP）是一种遗传和临床异质性视网膜病变， 疾病导致感光细胞死亡，最终完全失明。 然而，大多数遗传性视网膜变性的分子发病机制 直到这个日期仍然难以捉摸。X连锁视网膜色素变性（XIRP）账户 占所有RP的33%。X染色体连锁疾病视网膜炎 色素沉着3型，负责约75%的X-连锁RP，11 占所有RP形式的百分比，并且被认为是RP的最严重形式。 最近，导致RP3的遗传病变已被分子定义。 它们是由所谓的视网膜色素变性GT3基因突变引起的 调节子（RPGR）基因与RCC1同源，RCC1是一个核苷酸交换基因， RanGT的系数。迄今为止鉴定的所有RP3错义突变均位于 在RCC1同源结构域中。这种基因普遍表达， RPGR中的突变仅导致视觉表型，主要限于 视网膜。我们已经鉴定了几种视网膜RPGR相互作用蛋白亚型 来源于在体外和体内与RPGR相互作用的相同基因， 这些相互作用被人类RP3疾病相关的错义所消除 突变。RPGR及其新型视网膜底物同种型共定位于视网膜中， 杆状光感受器的外节。因此，新的RPGR底物是 命名为RPGR相互作用蛋白（RPGRIPs）。此外，人类RPGRIP基因 与RP 16基因座共定位。RPGRIP包含非常长的可变卷曲螺旋 与参与囊泡运输的蛋白质具有同源性的结构域， 保守的球状和C末端RPGR相互作用结构域，表明 这些蛋白质介导囊泡转运相关过程。的目标 这项建议是为了了解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的突变和新型RPGRIPs的生物学作用。