Search

Leber congenital amaurosis (LCA) encompasses a set of early-onset blinding diseases that are characterized by vision loss, involuntary eye movement, and nonrecordable electroretinogram (ERG). At least 19 genes are associated with LCA, which is typically recessive; however, mutations in homeodomain transcription factor CRX lead to an autosomal dominant form of LCA. The mechanism of CRX-associated LCA is not understood. Here, we identified a spontaneous mouse mutant with a frameshift mutation in Crx ([Crx.sup.Rip]). We determined that [Crx.sup.Rip] is a dominant mutation that results in congenital blindness with nonrecordable response by ERG and arrested photoreceptor differentiation with no associated degeneration. Expression of LCA-associated dominant CRX frameshift mutations in mouse retina mimicked the [Crx.sup.Rip] phenotype, which was rescued by overexpression of WT CRX. Whole-transcriptome profiling using deep RNA sequencing revealed progressive and complete loss of rod differentiation factor NRL in [Crx.sup.Rip] retinas. Expression of NRL partially restored rod development in [Crx.sup.Rip]/+ mice. We show that the binding of homeobox transcription factor OTX2 at the Nrl promoter was obliterated in [Crx.sup.Rip] mice and ectopic expression of OTX2 rescued the rod differentiation defect. Together, our data indicate that OTX2 maintains Nrl expression in developing rods to consolidate rod fate. Our studies provide insights into CRX mutation-associated congenital blindness and should assist in therapeutic design., Introduction Inherited retinal degenerative diseases exhibit tremendous clinical and genetic heterogeneity, with almost 200 genes identified so far (Retinal Information Network) (1). In the 19th century, Theodor Leber described the [...]

Molecular decision‐makers of photoreceptor (PRC) membrane organization and gene regulation are critical to understanding sight and retinal degenerations that lead to blindness. Using Mfrprd6mice, which develop PRC degeneration, we uncovered that membrane‐type frizzled‐related protein (MFRP) participates in docosahexaenoic acid (DHA, 22:6) enrichment in a manner similar to adiponectin receptor 1 (AdipoR1). Untargeted imaging mass spectrometry demonstrates cell‐specific reduction of phospholipids containing 22:6 and very long‐chain polyunsaturated fatty acids (VLC‐PUFAs) in Adipor1−/−and Mfrprd6 retinas. Gene expression of pro‐inflammatory signaling pathways is increased and gene‐encoding proteins for PRC function decrease in both mutants. Thus, we propose that both proteins are necessary for retinal lipidome membrane organization, visual function, and to the understanding of the early pathology of retinal degenerative diseases. [ABSTRACT FROM AUTHOR]