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Dennis M. Maddox, Sakae Ikeda, Akihiro Ikeda, Weidong Zhang, Mark P. Krebs, Patsy M. Nishina, Jürgen K. Naggert; An Allele of Microtubule-Associated Protein 1A (Mtap1a) Reduces Photoreceptor Degeneration in Tulp1 and Tub Mutant Mice. Invest. Ophthalmol. Vis. Sci. 2012;53(3):1663-1669. doi: 10.1167/iovs.11-8871.
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© ARVO (1962-2015); The Authors (2016-present)
To identify genes that modify photoreceptor cell loss in the retinas of homozygous Tulp1tm1Pjn and Tubtub mice, which exhibit juvenile retinitis pigmentosa.
Modifier loci were identified by genetic quantitative trait locus analysis. F2 Tulp1tm1Pjn/tm1Pjn mutant mice from a B6-Tulp1tm1Pjn/tm1Pjn × AKR/J intercross were genotyped with a panel of single nucleotide polymorphism markers and phenotyped by histology for photoreceptor nuclei remaining at 9 weeks of age. Genotype and phenotype data were correlated and examined with Pseudomarker 2.02 using 128 imputations to map modifier loci. Thresholds for the 63%, 10%, 5%, and 1% significance levels were obtained from 100 permutations. A significant, protective candidate modifier was identified by bioinformatic analysis and confirmed by crossing transgenic mice bearing a protective allele of this gene with Tulp1- and Tub-deficient mice.
A significant, protective modifier locus on chromosome 2 and a suggestive locus on chromosome 13 that increases photoreceptor loss were identified in a B6-Tulp1tm1Pjn/tm1Pjn × AKR/J intercross. The chromosome 2 locus mapped near Mtap1a, which encodes a protein associated with microtubule-based intracellular transport and synapse function. The protective Mtap1a129P2/OlaHsd allele was shown to reduce photoreceptor loss in both Tulp1tm1Pjn/tm1Pjn and Tubtub/tub mice.
It was demonstrated that the gene Mtap1a, which modifies hearing loss in Tubtub/tub mice, also modifies retinal degeneration in Tubtub/tub and Tulp1tm1Pjn/tm1Pjn mice. These results suggest that functionally nonredundant members of the TULP family (TUB and TULP1) share a common functional interaction with MTAP1A.
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