title: Differential dimerization of variants linked to enhanced S-cone sensitivity syndrome (ESCS) located in the NR2E3 ligand-binding domain.
abstract: NR2E3 encodes the photoreceptor-specific nuclear hormone receptor that acts as a repressor of cone-specific gene expression in rod photoreceptors, and as an activator of several rod-specific genes. Recessive variants located in the ligand-binding domain (LBD) of NR2E3 cause enhanced short wavelength sensitive- (S-) cone syndrome (ESCS), a retinal degeneration characterized by an excess of S-cones and non-functional rods. We analyzed the dimerization properties of NR2E3 and the effect of disease-causing LBD missense variants by bioluminescence resonance energy transfer (BRET(2) ) protein interaction assays. Homodimerization was not affected in presence of p.A256V, p.R039G, p.R311Q, and p.R334G variants, but abolished in presence of p.L263P, p.L336P, p.L353V, p.R385P, and p.M407K variants. Homology modeling predicted structural changes induced by NR2E3 LBD variants. NR2E3 LBD variants did not affect interaction with CRX, but with NRL and rev-erbα/NR1D1. CRX and NRL heterodimerized more efficiently together, than did either with NR2E3. NR2E3 did not heterodimerize with TLX/NR2E1 and RXRα/NR2C1. The identification of a new compound heterozygous patient with detectable rod function, who expressed solely the p.A256V variant protein, suggests a correlation between LBD variants able to form functional NR2E3 dimers and atypical mild forms of ESCS with residual rod function.
authors.affiliation: IRO-Institute for Research in Ophthalmology, Sion, Switzerland.|EPFL-Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Désirée
authors.initials: D
authors.lastname: von Alpen
authors.affiliation: Jules-Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland.
authors.forename: Hoai Viet
authors.initials: HV
authors.lastname: Tran
authors.affiliation: Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guex
authors.affiliation: IRO-Institute for Research in Ophthalmology, Sion, Switzerland.
authors.forename: Giulia
authors.initials: G
authors.lastname: Venturini
authors.affiliation: Jules-Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland.
authors.forename: Francis L
authors.initials: FL
authors.lastname: Munier
authors.affiliation: IRO-Institute for Research in Ophthalmology, Sion, Switzerland.|EPFL-Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Jules-Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Schorderet
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Schepens Eye Research Institute, Boston, Massachusetts.
authors.forename: Neena B
authors.initials: NB
authors.lastname: Haider
authors.affiliation: IRO-Institute for Research in Ophthalmology, Sion, Switzerland.|Jules-Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Escher
mesh_terms: D000293:Adolescent; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D002460:Cell Line; D004252:DNA Mutational Analysis; D015785:Eye Diseases, Hereditary / Q000175:diagnosis / Q000235:genetics*; D005136:Eye Proteins / Q000378:metabolism; D005451:Fluorescein Angiography; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D057093:Orphan Nuclear Receptors / Q000737:chemistry* / Q000235:genetics*; D010375:Pedigree; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D055503:Protein Multimerization; D012160:Retina / Q000378:metabolism; D012162:Retinal Degeneration / Q000175:diagnosis / Q000235:genetics*; D041623:Tomography, Optical Coherence; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014786:Vision Disorders / Q000175:diagnosis / Q000235:genetics*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D005136:Eye Proteins; D018398:Homeodomain Proteins; D008024:Ligands; C403073:NR2E3 protein, human; C490037:NRL protein, human; D057093:Orphan Nuclear Receptors; D015534:Trans-Activators; D014157:Transcription Factors; C109288:cone rod homeobox protein
keywords: NR2E3; genotype-phenotype correlation; photoreceptor development; retinal degeneration