title: Mutations in NR2E3 can cause dominant or recessive retinal degenerations in the same family.
abstract: NR2E3, 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.
authors.affiliation: Institut de Recherche en Ophtalmologie, Sion, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Escher
authors.forename: Peter
authors.initials: P
authors.lastname: Gouras
authors.forename: Raphaël
authors.initials: R
authors.lastname: Roduit
authors.forename: Leila
authors.initials: L
authors.lastname: Tiab
authors.forename: Sylvain
authors.initials: S
authors.lastname: Bolay
authors.forename: Tania
authors.initials: T
authors.lastname: Delarive
authors.forename: Shiming
authors.initials: S
authors.lastname: Chen
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Tsai
authors.forename: Masanori
authors.initials: M
authors.lastname: Hayashi
authors.forename: Jana
authors.initials: J
authors.lastname: Zernant
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Merriam
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mermod
authors.forename: Rando
authors.initials: R
authors.lastname: Allikmets
authors.forename: Francis L
authors.initials: FL
authors.lastname: Munier
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Schorderet
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D024202:Electrophoretic Mobility Shift Assay; D005192:Family Health; D005260:Female; D005799:Genes, Dominant; D005808:Genes, Recessive; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D057093:Orphan Nuclear Receptors; D010375:Pedigree; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000473:pathology; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C403073:NR2E3 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors