title: Novel NR2E3 mutations (R104Q, R334G) associated with a mild form of enhanced S-cone syndrome demonstrate compound heterozygosity.
abstract: OBJECTIVE
  We investigated the ophthalmic features of a mild form of enhanced S-cone syndrome (ESCS) in a 33-year-old Japanese female proband and 3 unaffected family members. A genetic analysis was performed.
  
  
  METHODS
  Genetic and observational case study.
  
  
  METHODS
  Fundus examinations, optical coherence tomography (OCT), Goldmann visual field (VF) perimetry, color vision tests, spectral sensitivity, and full-field and spectral electroretinography (ERG) were performed. Mutation screening of the NR2E3 gene, which encodes a photoreceptor-specific orphan nuclear receptor, was performed with polymerase chain reaction amplification and direct sequencing.
  
  
  METHODS
  Mutations in the NR2E3 gene, fundus photographs, OCT images, VFs, spectral sensitivity, and ERG findings.
  
  
  RESULTS
  The diagnosis of ESCS was made based on the distinctive spectral ERG findings: hypersensitivity to blue stimuli and hyposensitivity to red stimuli. The proband had good visual acuity, normal color vision, good central VFs, and nearly normal spectral sensitivity. Funduscopy showed degenerative lesions in the vascular arcades to the midperipheral retina. The OCT images showed a morphologically normal macular thickness. In the full-field ERG, low amplitudes of rod b-waves were detected. Waveforms between rod-plus-cone and cone ERGs were very similar. Mutation analysis identified 2 novel compound heterozygous missense mutations, p.R104Q and p.R334G, which reside in the DNA-binding domain (DBD) and ligand-binding domain (LBD), respectively. The unaffected parents carried one of these mutations each, consistent with autosomal recessive transmission.
  
  
  CONCLUSIONS
  Our study suggests that the expression of these 2 mutants of NR2E3, acting as a dimer, is correlated with a mild form of ESCS in that full foveal function and retinal laminar structure are maintained, and certain rod responses are present. This may be explained by the possibility that the heterodimers encoded by the 2 mutant alleles retain certain NR2E3 functions through the respective intact DBD and LBD.
authors.affiliation: Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan. taka@jikei.ac.jp
authors.forename: Takaaki
authors.initials: T
authors.lastname: Hayashi
authors.forename: Tamaki
authors.initials: T
authors.lastname: Gekka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Goto-Omoto
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Akiko
authors.initials: A
authors.lastname: Kubo
authors.forename: Kenji
authors.initials: K
authors.lastname: Kitahara
mesh_terms: D000328:Adult; D003119:Color Perception Tests; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005451:Fluorescein Angiography; D006579:Heterozygote; D006801:Humans; D020125:Mutation, Missense; D057093:Orphan Nuclear Receptors; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology*; D012162:Retinal Degeneration / Q000175:diagnosis / Q000235:genetics*; D017299:Rod Opsins / Q000235:genetics; D013577:Syndrome; D041623:Tomography, Optical Coherence; D014157:Transcription Factors / Q000235:genetics*; D058609:Visual Field Tests; D014794:Visual Fields
chemical_list: D005136:Eye Proteins; C403073:NR2E3 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D017299:Rod Opsins; D014157:Transcription Factors; C095853:short-wavelength opsin