Rao Kollu N, Zhang Wei, Li Linjing, Ronquillo Cecinio, Baehr Wolfgang, Khanna Hemant
Department of Ophthalmology, Horae Gene Therapy Center, UMASS Medical School, Worcester, MA, USA and.
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA.
Hum Mol Genet. 2016 May 15;25(10):2005-2012. doi: 10.1093/hmg/ddw075. Epub 2016 Mar 2.
Mutations in RPGR (retinitis pigmentosa GTPase regulator) are the most common cause of X-linked RP, a severe blindness disorder. RPGR mutations result in clinically variable disease with early- to late-onset phenotypic presentation. Molecular mechanisms underlying such heterogeneity are unclear. Here we show that phenotypic expression of Rpgr-loss in mice is influenced genetically by the loss of Cep290, a human ciliopathy gene. We found that Rpgr mice with a heterozygous hypomorphic allele of Cep290 (Cep290) but not of a heterozygous null allele of Cep290 (Cep290) or of other ciliopathy genes, Rpgrip1, Nphp1, Nphp4 and Nphp5, exhibit relatively early onset (by 3 months of age) retinal degeneration and dysfunction when compared with the onset at ∼7 months of age in the Rpgr mice. We also observed disorganized photoreceptor outer-segment morphology and defective trafficking of opsins in the Rpgr::Cep290 mice. Together with a physical interaction between RPGR and the C-terminal domain of CEP290, our data suggest that RPGR and CEP290 genetically interact and highlight the involvement of hypomorphic alleles of genes as potential modifiers of heterogeneous retinal ciliopathies.
RPGR（色素性视网膜炎GTP酶调节蛋白）突变是X连锁视网膜色素变性（一种严重的失明疾病）的最常见病因。RPGR突变导致临床症状多样的疾病，具有早发性至迟发性的表型表现。这种异质性背后的分子机制尚不清楚。在此，我们表明小鼠中Rpgr缺失的表型表达在遗传上受人类纤毛病基因Cep290缺失的影响。我们发现，与Rpgr小鼠约7个月龄发病相比，携带Cep290杂合次等位基因（Cep290）而非Cep290杂合无效等位基因或其他纤毛病基因Rpgrip1、Nphp1、Nphp4和Nphp5的Rpgr小鼠表现出相对较早（3个月龄）的视网膜变性和功能障碍。我们还观察到Rpgr::Cep290小鼠中光感受器外段形态紊乱以及视蛋白运输缺陷。结合RPGR与CEP290 C末端结构域之间的物理相互作用，我们的数据表明RPGR和CEP290在遗传上相互作用，并突出了基因次等位基因作为异质性视网膜纤毛病潜在修饰因子的作用。
