A Novel Form of Transducin-Dependent Retinal Degeneration: Accelerated Retinal Degeneration in the Absence of Rod Transducin

Brill, Elliott; Malanson, Katherine; Radu, Roxana A.; Boukharov, Natalia V.; Wang, Zhongyan; Chung, Hae-Kyung; Lloyd, Monte; Bok, Dean; Travis, Gabriel H.; Obin, Martin S.; Lem, Janis

doi:10.1167/iovs.06-1402

Cited by 17 publications

(11 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This discrepancy may be due to differences in experimental protocols (cyclic light-reared for P347S vs. dark-reared for Q344ter) or the nature of the rhodopsin mutation itself. In the P347S mice lipofuscin fluorophores were found to be elevated, perhaps due to a faster decay of MII to apo-opsin and free all-trans-retinaldehyde [57]. We did not observe an accumulation of lipofucsin in the Q344ter mice.…”

Section: Discussioncontrasting

confidence: 62%

Q344ter Mutation Causes Mislocalization of Rhodopsin Molecules That Are Catalytically Active: A Mouse Model of Q344ter-Induced Retinal Degeneration

Concepcion

Chen

2010

PLoS ONE

View full text Add to dashboard Cite

Q344ter is a naturally occurring rhodopsin mutation in humans that causes autosomal dominant retinal degeneration through mechanisms that are not fully understood, but are thought to involve an early termination that removed the trafficking signal, QVAPA, leading to its mislocalization in the rod photoreceptor cell. To better understand the disease mechanism(s), transgenic mice that express Q344ter were generated and crossed with rhodopsin knockout mice. Dark-reared Q344terrho+/− mice exhibited retinal degeneration, demonstrating that rhodopsin mislocalization caused photoreceptor cell death. This degeneration is exacerbated by light-exposure and is correlated with the activation of transducin as well as other G-protein signaling pathways. We observed numerous sub-micrometer sized vesicles in the inter-photoreceptor space of Q344terrho+/− and Q344terrho−/− retinas, similar to that seen in another rhodopsin mutant, P347S. Whereas light microscopy failed to reveal outer segment structures in Q344terrho−/− rods, shortened and disorganized rod outer segment structures were visible using electron microscopy. Thus, some Q344ter molecules trafficked to the outer segment and formed disc structures, albeit inefficiently, in the absence of full length wildtype rhodopsin. These findings helped to establish the in vivo role of the QVAPA domain as well as the pathways leading to Q344ter-induced retinal degeneration.

show abstract

Section: Discussioncontrasting

confidence: 62%

Q344ter Mutation Causes Mislocalization of Rhodopsin Molecules That Are Catalytically Active: A Mouse Model of Q344ter-Induced Retinal Degeneration

Concepcion

Chen

2010

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…Similarly, aberrant rhodopsin transport has been implicated in photoreceptor degeneration in transgenic mice carrying the proline 347 to serine mutation, 30 a mutation affecting the C-terminus of rhodopsin that shows no functional abnormality in in vitro studies, but is associated with more severe disease in humans than other autosomal dominant rhodopsin mutations. On the one hand, Smardzija et al 39 showed that photoreceptor loss was reduced in VPP mice that lacked transducin expression, whereas Brill et al 40 showed that the absence of transducin expression had no affect on the rate of photoreceptor loss. 30 Some rhodopsin mutations, especially Class II mutations, are predicted to cause photoreceptor death by being constitutively active.…”

Section: A Animal Models With Genetic Mutationsmentioning

confidence: 99%

Animal Models of Retinal Disease

Fletcher

Jobling

Vessey

et al. 2011

Progress in Molecular Biology and Translational Science

View full text Add to dashboard Cite

“…There have been reported that suggested defects in protein translocation could increase the susceptibility of light-induced photoreceptor degeneration (Chen et al, 1999; Kong et al, 2006; Peng et al, 2008) and prolonged activation of the phototransduction cascade has been associated with photoreceptor degeneration (Brill et al, 2007; Chen et al, 1999; Xu et al, 1997; Lem and Fain et al, 2004). Shifting the threshold of transducin translocation to a higher level, thus, may increase the metabolic stress in rods under conditions of bright illumination; and make these rods vulnerable to light-induced degeneration even under moderate light intensities.…”

Section: Discussionmentioning

confidence: 99%

Photoreceptors in whirler mice show defective transducin translocation and are susceptible to short-term light/dark changes-induced degeneration

Tian

Wang

Delimont

et al. 2014

Experimental Eye Research

View full text Add to dashboard Cite

Usher syndrome combines congenital hearing loss and retinitis pigmentosa (RP). Mutations in the whirlin gene (DFNB31/WHRN) cause a subtype of Usher syndrome (USH2D). Whirler mice have a defective whirlin gene. They have inner ear defects but usually do not develop retinal degeneration. Here we report that, in whirler mouse photoreceptors, the light-activated rod transducin translocation is delayed and its activation threshold is shifted to a higher level. Rhodopsin mis-localization is observed in rod inner segments. Continuous moderate light exposure can induce significant rod photoreceptor degeneration. Whirler mice reared under a 1500 lux light/dark cycle also develop severe photoreceptor degeneration. Previously, we have reported that shaker1 mice, a USH1B model, show moderate light-induced photoreceptor degeneration with delayed transducin translocation. Here, we further show that, in both whirler and shaker1 mice, short-term moderate light/dark changes can induce rod degeneration as severe as that induced by continuous light exposure. The results from shaker1 and whirler mice suggest that defective transducin translocation may be functionally related to light-induced degeneration, and these two symptoms may be caused by defects in Usher protein function in rods. Furthermore, these results indicate that both Usher syndrome mouse models possess a light-induced retinal phenotype and may share a closely related pathobiological mechanism.

show abstract

A Novel Form of Transducin-Dependent Retinal Degeneration: Accelerated Retinal Degeneration in the Absence of Rod Transducin

Cited by 17 publications

References 70 publications

Q344ter Mutation Causes Mislocalization of Rhodopsin Molecules That Are Catalytically Active: A Mouse Model of Q344ter-Induced Retinal Degeneration

Q344ter Mutation Causes Mislocalization of Rhodopsin Molecules That Are Catalytically Active: A Mouse Model of Q344ter-Induced Retinal Degeneration

Animal Models of Retinal Disease

Photoreceptors in whirler mice show defective transducin translocation and are susceptible to short-term light/dark changes-induced degeneration

Contact Info

Product

Resources

About