Chakraborty Dibyendu, Conley Shannon M, Zulliger Rahel, Naash Muna I
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Department of Biomedical Engineering, University of Houston, Houston, TX, USA.
Hum Mol Genet. 2016 Aug 15;25(16):3500-3514. doi: 10.1093/hmg/ddw193. Epub 2016 Jun 29.
Peripherin 2 (Prph2) is a photoreceptor tetraspanin, and deletion of codon 153 (K153Δ) leads to retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in the same family. To study this variability, we generated a K153Δ-Prph2 knockin mouse. K153Δ-Prph2 cannot form the complexes required for outer segment formation, and in cones cannot interact with its binding partner rod outer segment membrane protein 1. K153Δ causes dominant defects in rod and cone function; however, rod but not cone ultrastructure is improved by the presence of K153Δ-Prph2. Likewise, supplementation of K153Δ heterozygotes with WT-Prph2 results in structural but not functional improvements. These results support the idea that mutations may differentially affect Prph2's role as a structural component, and its role as a functional protein key for organizing membrane domains for cellular signalling. These roles may be different in rods and cones, thus contributing to the phenotypic heterogeneity that characterizes diseases associated with Prph2 mutations.
外周蛋白2（Prph2）是一种光感受器四跨膜蛋白，密码子153缺失（K153Δ）会导致同一家族出现色素性视网膜炎、图案性营养不良和黄斑病变。为了研究这种变异性，我们构建了K153Δ-Prph2基因敲入小鼠。K153Δ-Prph2无法形成外段形成所需的复合物，在视锥细胞中也无法与其结合伴侣视杆外段膜蛋白1相互作用。K153Δ在视杆和视锥功能上导致显性缺陷；然而，K153Δ-Prph2的存在改善了视杆而非视锥的超微结构。同样，用野生型Prph2补充K153Δ杂合子会导致结构改善，但功能并未改善。这些结果支持这样一种观点，即突变可能会不同程度地影响Prph2作为结构成分的作用，以及其作为组织细胞信号传导膜结构域的功能蛋白关键的作用。这些作用在视杆和视锥中可能不同，从而导致与Prph2突变相关疾病所特有的表型异质性。
