Dataset Information

Effect of heterozygous RhoQ344X/+ mutation on gene expression in postnatal day (P) 35 mouse retina

ABSTRACT: Class I rhodopsin mutations are known for some of the most severe forms of vision impairments in dominantly inherited rhodopsin retinitis pigmentosa. They disrupt the VxPx transport signal, which is required for the proper localization of rhodopsin to the outer segments. While various studies have focused on the light-dependent toxicity of mutant rhodopsin, it remains unclear whether and how these mutations exert dominant-negative effects. Using the class I RhoQ344X rhodopsin knock-in mouse model, we characterized the expression of rhodopsin and other genes by RNA sequencing and qPCR. Those studies indicated that rhodopsin is the most prominently downregulated photoreceptor-specific gene in RhoQ344X/+ mice. Rhodopsin is downregulated significantly prior to the onset of rod degeneration, whereas downregulation of other phototransduction genes, transducinα, and Pde6α, occur after the onset and correlate with the degree of rod cell loss. Those studies indicated that the mutant rhodopsin gene causes downregulation of wild-type rhodopsin, imposing a mRNA-level dominant negative effect. Moreover, it causes downregulation of the mutant mRNA itself, mitigating the toxicity. The observed dominant effect is likely common among rhodopsin retinitis pigmentosa as we found a similar rhodopsin downregulation in the major class II rhodopsin mutant model, RhoP23H/+ mice, in which mutant rhodopsin is prone to misfold. Potentially due to mitigated toxicity by reduced rhodopsin expression, RhoQ344X/+ mice did not exhibit light-dependent exacerbation of rod degeneration, even after continuous exposure of mice for 5 days at 3000 lux. Thus, this study describes a novel form of dominant negative effect in inherited neurodegenerative disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE293123 | GEO | 2025/09/07

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Retinal degeneration is the leading cause of irreversible blindness. Retinitis pigmentosa (RP) is a genetically heterogenous group of diseases. In the United States, approximately one in 4000 individuals is affected. RP begins with the loss of night vision due to the loss of rod photoreceptor cells. The disease progresses slowly with the loss of peripheral vision, and eventually leads to complete debilitating and irreversible blindness. The first mutation associated with human RP was identified in the gene encoding rhodopsin, the G-protein coupled receptor of rod photoreceptor cells. Mutations within the rhodopsin gene account for significant portion of RP cases. Specifically, mutations of the proline at residue 347 in rhodopsin have been linked to human RP. We are fortunate to have access to the P347S rhodopsin mutant mice. These mice represent an excellent transgenic mouse model of retinal degeneration. The P347S rhodopsin mutation is one of the best studied mutations, yet the mechanism by which the mutation causes degeneration is still unknown. One study has demonstrated that galectin-1 plays a role in degeneration of neuronal processes (1) and another study has shown that expression level of galectin-3 is elevated in retinas of patients with age-related macular degeneration. These studies in conjunction with the availibility of the P347S mutant mice have provided impetus to examine the pathogenesis of retinal degeneration in the context of the possible role of glycans and glycan-binding proteins. The time course of photoreceptor degeneration in the P347S mouse model has been carefully studied. In these mice, degeneration is barely detectable at 1 month of age, yet biochemical evidence suggests that the rod photoreceptor cells have already begun to die. At 4 months of age, approximately half of the rod photoreceptor cells have degenerated. To distinguish involvement of glycogens at the various stages of retinal degeneration, we have collected retinas of wild type and the mutant mice at four time points (1, 2, 3, and 4 months of age). This will allow us to identify the genes that target early, mid- and late stages of the retinal degeneration process. Thus we request the analysis of total 24 samples as specified below: Age Group (months) Mice No of samples at each time point 1 Wild type 3 2 Wild type 3 3 Wild type 3 4 Wild type 3 1 P347S 3 2 P347S 3 3 P347S 3 4 P347S 3 Total 24.

Dataset Information

Effect of heterozygous RhoQ344X/+ mutation on gene expression in postnatal day (P) 35 mouse retina

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets