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OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness
Jerome E. Roger, … , Bo Chang, Anand Swaroop
Jerome E. Roger, … , Bo Chang, Anand Swaroop
Published January 2, 2014
Citation Information: J Clin Invest. 2014;124(2):631-643. https://doi.org/10.1172/JCI72722.
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Research Article Ophthalmology Article has an altmetric score of 16

OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness

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Abstract

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 (CrxRip). We determined that CrxRip 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 CrxRip 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 CrxRip retinas. Expression of NRL partially restored rod development in CrxRip/+ mice. We show that the binding of homeobox transcription factor OTX2 at the Nrl promoter was obliterated in CrxRip 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.

Authors

Jerome E. Roger, Avinash Hiriyanna, Norimoto Gotoh, Hong Hao, Debbie F. Cheng, Rinki Ratnapriya, Marie-Audrey I. Kautzmann, Bo Chang, Anand Swaroop

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Figure 6

RNA-Seq analysis of P2 and P21 CrxRip retinas reveals a progressive loss of expression of rod-specific genes.

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RNA-Seq analysis of P2 and P21 CrxRip retinas reveals a progressive loss...
(A) Venn diagrams comparing DEGs identified as significant (fold change ≥ 2, adjusted P value ≤ 0.05, and a mean normalized expression of 5 in at least 1 of the groups compared) between WT and CrxRip/+, Crx–/–, and Nrl–/– retinas. (B and C) Heat maps and hierarchical clustering dendrogram from 24 and 460 DEGs at (B) P2 and (C) P21, respectively. Genes showing a minimum fold change of 2 between Crx+/+ and CrxRip/+ retinas, with adjusted P values of less than or equal to 0.05 and mean of normalized expression of more than or equal to 5 were selected. The expression value of each sample is represented with blue indicating lowest expression, with increasing expression from gray to red for the highest expression. Expression value is in log2 scale.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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