Differential dimerization of variants linked to enhanced S-cone sensitivity syndrome (ESCS) located in the NR2E3 ligand-binding domain

Hum Mutat. 2015 Jun;36(6):599-610. doi: 10.1002/humu.22775. Epub 2015 Apr 27.

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.

Keywords: NR2E3; genotype-phenotype correlation; photoreceptor development; retinal degeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Cell Line
  • DNA Mutational Analysis
  • Eye Diseases, Hereditary / diagnosis
  • Eye Diseases, Hereditary / genetics*
  • Eye Proteins / metabolism
  • Fluorescein Angiography
  • Homeodomain Proteins / metabolism
  • Humans
  • Ligands
  • Male
  • Models, Molecular
  • Mutation
  • Orphan Nuclear Receptors / chemistry*
  • Orphan Nuclear Receptors / genetics*
  • Pedigree
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Domains and Motifs / genetics*
  • Protein Multimerization*
  • Retina / metabolism
  • Retinal Degeneration / diagnosis
  • Retinal Degeneration / genetics*
  • Tomography, Optical Coherence
  • Trans-Activators / metabolism
  • Transcription Factors / metabolism
  • Vision Disorders / diagnosis
  • Vision Disorders / genetics*

Substances

  • Basic-Leucine Zipper Transcription Factors
  • Eye Proteins
  • Homeodomain Proteins
  • Ligands
  • NR2E3 protein, human
  • NRL protein, human
  • Orphan Nuclear Receptors
  • Trans-Activators
  • Transcription Factors
  • cone rod homeobox protein

Supplementary concepts

  • Enhanced S-Cone Syndrome