Moleclar Pathogenesis of Retinitis Pigmentosa Type 3

描述(由申请人提供)： 视网膜色素变性(RP)是一种遗传性和临床异质性视网膜。 疾病会导致感光细胞死亡，最终导致完全失明。 然而，大多数形式的遗传性视网膜变性的分子发病机制 直到今天仍然难以捉摸。X-连锁视网膜色素变性(XIRP)帐户 适用于高达33%的所有形式的RP。X连锁疾病--视网膜炎 色素型3型，负责大约75%的X连锁RP，11 占所有RP形式的百分比，它被认为是最严重的RP形式。 最近，导致RP3的遗传损伤已经在分子上得到了定义。 它们是由所谓的视网膜色素变性GTP酶突变引起的 RPGR基因与核苷酸交换基因RCC1的同源性 RanGTP酶的因子。到目前为止发现的所有RP3错义突变都已定位 在RCC1-同源结构域中。这种基因无处不在地表达，但 RPGR的突变只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 来源于在体外和体内与RPGR相互作用的同一基因，以及 这些相互作用被人类RP3疾病相关的错义所消除 突变。RPGR及其新的视网膜底物异构体(S)共定位于 杆状感光器的外节。因此，新型的RPGR底物是 指定RPGR相互作用蛋白(RPGRIP)。此外，人类RPGRIP基因 与RP16基因座共定位。RPGRIP包含非常长的可变盘绕线圈 与参与囊泡运输的蛋白质同源的结构域和 保守的、球形的和C末端的RPGR相互作用结构域，表明 这些蛋白质介导与囊泡运输相关的过程。的目标 这一建议是为了了解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的突变和新的RPGRIPs的生物学作用。

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.