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S. Panda, V. Piamonte, B. M. Steffy, T. Wiltshire, N. Tanaka, S. Gill, L. Tarantino; A Novel Point Mutation in the Mouse Nrl Gene Causes Developmental Reprogramming of the Retina. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4000.
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© ARVO (1962-2015); The Authors (2016-present)
Congenital ocular defects in mice have served as an excellent model to understand molecular bases of human diseases. To identify novel mutations leading to abnormal retina development or retina degeneration we undertook phenotypic screen of ENU mutagenized mice. This approach often yields subtle missense mutations that closely resemble respective causal mutations underlying human diseases.
Families of mice derived from founder C57Bl/6J male mice mutagenized with ENU were screened for congenital ocular defects by indirect ophthalmoscopy. Multiple members of a mutant family showed signs of retina degeneration and the family was selected for map based cloning. Genome-wide linkage analysis and position based cloning approaches were used to identify the causal mutation. Immunohistochemcial examination of the retina was performed to identify specific cellular defects in the mutant. Genome-wide transcriptional profiling of the retina was performed to identify specific gene expression changes in the mutant mouse.
The mutant was autosomal recessive and fully penetrant, which exhibits severe loss of rod outer segment at 8 weeks of age. The mice are born with no other obvious developmental, physiological or reproductive abnormality. Positional cloning revealed a missense mutation in the protein coding region of the gene encoding basic motif/leucine zipper domain containing protein Nrl that changes a conserved residue in the DNA binding domain. The amino acid mutation likely renders the protein non-functional as the mutant mice phenocopy several key phenotypes of the homozygous loss-of-function allele of Nrl, including loss of rhodopsin expression and loss of several markers of rod photoreceptors. There is also a significant increase in the mRNA level of S-cone opsin and other cone photoreceptor markers. Interestingly, the mutant also showed no detectable level of Nrl mRNA in the retina.
Missense mutation in the Nrl gene in a region where many disease causing human mutations have been identified offers an ideal animal model for the human disease. The significant reduction in Nrl mRNA level in the mutant implies the mutation either causes rapid degradation of the RNA or functional NRL protein product is necessary to maintain its own transcription.
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