A new rhodopsin R135W mutation induces endoplasmic reticulum stress and apoptosis in retinal pigment epithelial cells

Abstract

Rhodopsin mutations are associated with the autosomal‐dominant form of retinitis pigmentosa (RP). Here we report simultaneous occurrence of RP associated with bilateral nanophthalmos and acute angle‐closure glaucoma in patient with a new mutation in rhodopsin (R135W). ARPE‐19 cells were transfected with myc‐tagged wild‐type (WT) and R135W rhodopsin constructs. The half‐life of WT and R135W rhodopsin was analyzed via cycloheximide chase analysis. We found that R135W rhodopsin was accumulated in the endoplasmic reticulum (ER) and induced unfolded protein response (UPR) and apoptosis. Moreover, chaperone HSP70 alleviated ER stress and prevented apoptosis induced by R135W rhodopsin by attenuating UPR signaling. These findings reveal the novel pathogenic mechanism of RP and suggest that chaperone HSP70 has potential therapeutic significance for RP.

Association between retinitis pigmentosa and an increased risk of primary angle closure glaucoma: A population-based cohort study

“…Mackay, Buys, Wang, Mandel, and Yu et al also described these associations in case reports [6,18,20,21,30]. Genetic mutations such as membrane frizzled-related protein (MFRP) and rhodopsin (R135 W) have been identified as predisposing factors of this syndrome [6,31]. In our study, the RP group had a higher prevalence of nanophthalmolos than the comparison group, although the number of cases were very low (3 and 5, respectively).…”

“…Ghose et al documented the simultaneous occurrence of nanophthalmos, angle closure glaucoma and retinitis pigmentosa as the triad of a new syndrome [29]. Mackay, Buys, Wang, Mandel, and Yu et al also described these associations in case reports [6,18,20,21,30]. Genetic mutations such as membrane frizzled-related protein (MFRP) and rhodopsin (R135 W) have been identified as predisposing factors of this syndrome [6,31].…”

“…Elder et al even considered that the association between RP and PACG was coincidental because of its rarity [5]. However, some studies have demonstrated that the association between RP and PACG is related to nanophthalmos, cataract, and lens subluxation in RP, which are all predisposing factors of PACG [1,4,6].…”

Lipid Dyshomeostasis and Inherited Cerebellar Ataxia

“…Interestingly, lipid disequilibrium in the ER membrane is closely related to ER stress [ 77 , 78 ] and Ca 2+ homeostasis [ 262 , 263 ]. Consistent with this, all three GPCR scramblases can cause ER stress and apoptosis when they are dysfunctional [ 264 – 266 ], suggesting that TMEM16K mutants probably cause ARCA3 through the same mechanism. Indeed, TMEM16K defects result in deranged Ca 2+ signaling [ 267 ] and Purkinje cell dysfunction [ 248 , 251 , 268 ].…”

SIK2 protects against renal tubular injury and the progression of diabetic kidney disease

“…The increased synthesis of Hsp70 is a hallmark of stressed cells and organisms, which functions as molecular chaperones to prevent protein misfolding and aggregation to maintain protein homeostasis [48]. Hsp70 has also been reported to alleviate ER stress and prevent apoptosis [49,50]. Consequently, we speculate that SIK2 might inhibit ER stress through the upregulation of Hsp70.…”