Human mutation

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1098-10043032009MarHuman mutationHum MutatMutations in NR2E3 can cause dominant or recessive retinal degenerations in the same family.342351342-5110.1002/humu.20858NR2E3, a photoreceptor-specific nuclear receptor (PNR), represses cone-specific genes and activates several rod-specific genes. In humans, mutations in NR2E3 have been associated with the recessively-inherited enhanced short-wavelength sensitive S-cone syndrome (ESCS) and, recently, with autosomal dominant (ad) retinitis pigmentosa (RP) (adRP). In the present work, we describe two additional families affected by adRP that carry a heterozygous c.166G>A (p.G56R) mutation in the NR2E3 gene. Functional analysis determined the dominant negative activity of the p.G56R mutant protein as the molecular mechanism of adRP. Interestingly, in one pedigree, the most common causal variant for ESCS (p.R311Q) cosegregated with the adRP-linked p.G56R mutation, and the compound heterozygotes exhibited an ESCS-like phenotype, which in 1 of the 2 cases was strikingly "milder" than the patients carrying the p.G56R mutation alone. Impaired repression of cone-specific genes by the corepressors atrophin-1 (dentatorubral-pallidoluysian atrophy [DRPLA] gene product) and atrophin-2 (arginine-glutamic acid dipeptide repeat [RERE] protein) appeared to be a molecular mechanism mediating the beneficial effect of the p.R311Q mutation. Finally, the functional dominance of the p.R311Q variant to the p.G56R mutation is discussed.2008 Wiley-Liss, Inc.EscherPascalPInstitut de Recherche en Ophtalmologie, Sion, Switzerland.GourasPeterPRoduitRaphaëlRTiabLeilaLBolaySylvainSDelariveTaniaTChenShimingSTsaiChih-ChengCCHayashiMasanoriMZernantJanaJMerriamJoanna EJEMermodNicolasNAllikmetsRandoRMunierFrancis LFLSchorderetDaniel FDFengR01 EY013435EYNEI NIH HHSUnited StatesR01 EY015293-03EYNEI NIH HHSUnited StatesR01 EY012543-09EYNEI NIH HHSUnited StatesR01 EY015293EYNEI NIH HHSUnited StatesEY015293EYNEI NIH HHSUnited StatesEY12543EYNEI NIH HHSUnited StatesR01 EY012543EYNEI NIH HHSUnited StatesEY13435EYNEI NIH HHSUnited StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov't

United StatesHum Mutat92154291059-77940NR2E3 protein, human0Orphan Nuclear Receptors0Receptors, Cytoplasmic and Nuclear0Transcription FactorsIMAdolescentAdultAgedAmino Acid SequenceAnimalsCell LineElectrophoretic Mobility Shift AssayFamily HealthFemaleGenes, DominantGenes, RecessiveGenotypeHumansMaleMiceMice, Inbred C57BLMolecular Sequence DataMutationOrphan Nuclear ReceptorsPedigreeProtein BindingReceptors, Cytoplasmic and NucleargeneticsmetabolismRetinal DegenerationgeneticspathologyRetinitis PigmentosageneticspathologySequence Homology, Amino AcidTranscription FactorsgeneticsmetabolismYoung Adult200811149020095299020081114902013520ppublish19006237NIHMS65532PMC365813910.1002/humu.20858Akhmedov NB, Piriev NI, Chang B, Rapoport AL, Hawes NL, Nishina PM, Nusinowitz S, Heckenlively JR, Roderick TH, Kozak CA. A deletion in a photoreceptor-specific nuclear receptor mRNA causes retinal degeneration in the rd7 mouse. Proc. Natl. Acad. Sci. 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