The Alter Retina: Alternative Splicing of Retinal Genes in Health and Disease

Abstract

Alternative splicing of mRNA is an essential mechanism to regulate and increase the diversity of the transcriptome and proteome. Alternative splicing frequently occurs in a tissue- or time-specific manner, contributing to differential gene expression between cell types during development. Neural tissues present extremely complex splicing programs and display the highest number of alternative splicing events. As an extension of the central nervous system, the retina constitutes an excellent system to illustrate the high diversity of neural transcripts. The retina expresses retinal specific splicing factors and produces a large number of alternative transcripts, including exclusive tissue-specific exons, which require an exquisite regulation. In fact, a current challenge in the genetic diagnosis of inherited retinal diseases stems from the lack of information regarding alternative splicing of retinal genes, as a considerable percentage of mutations alter splicing or the relative production of alternative transcripts. Modulation of alternative splicing in the retina is also instrumental in the design of novel therapeutic approaches for retinal dystrophies, since it enables precision medicine for specific mutations.

Goat AKAP12: Indel Mutation Detection, Association Analysis With Litter Size and Alternative Splicing Variant Expression

“…Importantly, for the AKAP12-AS2 13-bp indel locus, the expression levels of homozygote DD were significantly lower than that of individuals with heterozygote ID, in both testis and ovarian tissues, which is consistent with the negative effects of the 13-bp deletion on the reduced litter size. It has been well established that alternative splicing might affect gene expression and translation through splicing proteins and other regulatory factors, thus affecting gene functions (Ule and Blencowe, 2019;Aísa-Marín et al, 2021). Thus, it's tempting to speculate that the 13-bp indel variation affects the binding of miRNAs, which in turn affected gene expression, resulting in a phenotypic difference.…”

“…Alternative splicing (AS) events can lead to multiple splicing variants of a gene and production of proteins with diverse functions therefore are necessary and fundamental in analyzing organism complexity, evolutionary pathways, and metabolic activities (Ule and Blencowe, 2019;Aísa-Marín et al, 2021). Generally, alternative splicing affects gene transcription and translation through splicing proteins and their regulatory factors, thus affecting gene functions.…”

Expression and subcellular localization of USH1C/harmonin in the human retina provide insights into pathomechanisms and therapy

“…Tissue- and cell specific alternative splicing frequently occurs, which was also previously predicted for USH1C (Scanlan et al 1999; Pan et al, 2017). In comparison to other tissues, the neuronal retina displays the highest level of alternative splicing events (Aisa-Marin et al, 2021; Zelinger & Swaroop, 2018). The extremely complex splicing programs of the retina are regulated by retina-specific splicing factors which are essential for retinal function and maintenance (Murphy et al, 2015; Ling et al, 2020; Sundar et al, 2021).…”

“…Tissue- and cell specific alternative splicing frequently occurs, previously also predicted for USH1C (36, 49). In comparison to other tissues, the neuronal retina displays the highest level of alternative splicing events (50, 51). Splicing programs are essential for retinal function and maintenance, and are regulated in an extremely complex way by retina-specific splicing factors (52-54).…”

RNA-Binding Proteins and Alternative Splicing Genes Are Coregulated in Human Retinal Endothelial Cells Treated with High Glucose

“…RNA-binding proteins (RBPs) are vital regulators of an mRNA life cycle, including their transcription, splicing export, and transport to degradation, deadenylation, storage, silencing, and mRNA translation (protein synthesis) [ 17 , 18 ]. Along with the spliceosome complex, RBPs have a major role in creating cell-type-specific regulation of alternative splicing [ 10 , 19 , 20 ]. Previous researchers have revealed the regulatory role of zinc finger RNA-binding protein [ 21 ] and the ELAVL1 (or human antigen R (HuR)) RNA-binding protein [ 22 ] in DR.…”