Goldberg A F, Molday R S
Department of Biochemistry and Molecular-Biology, University of British Columbia, Vancouver, Canada.
Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13726-30. doi: 10.1073/pnas.93.24.13726.
Retinitis pigmentosa (RP) is a group of progressive retinal dystrophies that include the most common hereditary degenerative disease affecting the retina. Although most disease phenotypes appear to result from defects at single genetic loci (monogenic), at least one instance of RP appears to require a coinheritance of defects in the unlinked peripherin/rds and rom-1 alleles (digenic), which encode the polypeptide subunits of an oligomeric transmembrane protein complex present at photoreceptor outer segment disc rims. Sedimentation velocity analysis was performed upon the affected gene products expressed heterologously in COS-1 cells to examine the assembly of the subunit polypeptides. The results indicate that the missense peripherin/rds mutant, L185P, which segregates with instance of digenically inherited RP, is conditionally defective with respect to its subunit assembly. Unlike wild-type peripherin/rds, the L185P mutant does not form native-like homotetramers on its own; however, the L185P mutant can assemble with wild-type rom-1 to form a structurally normal heterotetrameric complex. These findings provide a novel molecular-based rationale for the unusual digenic disease inheritance pattern and offer insight into regions of peripherin/rds and rom-1, which contribute to subunit-subunit interactions.
视网膜色素变性（RP）是一组进行性视网膜营养不良疾病，其中包括影响视网膜的最常见遗传性退行性疾病。虽然大多数疾病表型似乎是由单个基因位点（单基因）的缺陷引起的，但至少有一例RP似乎需要未连锁的外周蛋白/视网膜变性慢（rds）和视网膜外膜蛋白1（rom-1）等位基因缺陷的共同遗传（双基因），这两个基因编码存在于光感受器外段盘边缘的寡聚跨膜蛋白复合物的多肽亚基。对在COS-1细胞中异源表达的受影响基因产物进行沉降速度分析，以检查亚基多肽的组装情况。结果表明，与双基因遗传的RP病例相关的错义外周蛋白/rds突变体L185P在亚基组装方面存在条件性缺陷。与野生型外周蛋白/rds不同，L185P突变体自身不能形成天然样同四聚体；然而，L185P突变体可以与野生型rom-1组装形成结构正常的异四聚体复合物。这些发现为这种不寻常的双基因疾病遗传模式提供了一种基于分子的新理论依据，并深入了解了外周蛋白/rds和rom-1中有助于亚基-亚基相互作用的区域。
