A novel mutation in the NR2E3 gene associated with Goldmann-Favre syndrome and vasoproliferative tumor of the retina

Abstract

Purpose: Various autosomal recessive retinal dystrophies are reported to be associated with mutations in nuclear receptor subfamily 2, group E, member 3 (NR2E3, also called PNR) gene. The present study proposed to understand the clinical and genetic characteristics of the family of a patient with an ocular phenotype consistent with Goldmann-Favre syndrome (GFS) and vasoproliferative tumors of the retina (VPTRs).

Methods: Twelve family members of the proband from three generations underwent complete ophthalmic examination, including best-corrected visual acuity with Snellen optotypes, tonometry, biomicroscopic examination, indirect ophthalmoscopy after pupillary dilatation, computerized perimetry, optical coherence tomography, fundus photography, intravenous fluorescein angiography, and electroretinography (ERG). All the study subjects underwent genetic analysis of the entire coding region of the NR2E3 gene with the bidirectional DNA sequencing approach. Hundred healthy individuals were screened for the variant.

Results: The phenotype of the proband had features of GFS with VPTRs. The tumors showed complete resolution with cryotherapy and transpupillary thermotherapy (TTT). Sequencing of the entire coding region of the NR2E3 gene in the proband revealed a novel homozygous c.1117 A>G variant that led to the amino acid change from aspartic acid to glycine at position 406 (p.D406G). This change was present in the homozygous state in affected family members and in the heterozygous state in unaffected family members, and was undetectable in the control subjects. The identified novel p.D406G homozygous mutation was at an evolutionarily highly conserved region and may possibly affect the protein function (Sorting Intolerant From Tolerant [SIFT] score = 0.00).

Conclusions: Patients with GFS may present with retinal VPTRs that respond to therapy with cryotherapy and TTT. Molecular genetic studies helped to identify a novel p.D406G mutation in the affected members, which will aid in confirming the diagnosis, for genetic counseling of family members and potentially provide some form of therapy for the affected patients.

Figure 1

Pedigree of the family in this study. The asterisk symbol represents the sequenced individuals in this study. The genotyping of alleles were shown below the individuals.

Figure 2

Pre and Post treatment LE color fundus photograph of the proband A: Pre-treatment montage fundus photograph of left eye. LE Fundus shows a healthy appearing optic nerve head with diffuse RPE degeneration with nummular pigment clumps and white dentritic peripheral vessels in mid peripheral region . Vascularized tumor mass with exudation and absent feeder vessels is seen in the supro-temporal periphery. B: Vascularized peripheral tumor with profuse exudation. C: 9 Up fundus photograph of LE showing vasoproliferative tumors with exudation in superior, suprotemporal, inferotemporal and inferior quadrants. D: Post-treatment fundus photograph. LE fundus showing complete regression of the tumor masses with treatment. (6 month post treatment).

Figure 3

Fundus fluorescein angiography of vasoproliferative tumor. FFA shows rapid filling of the dye in the early phase, with the lesion becoming increasingly hyperfluorescent, and profuse and diffuse leakage of dye in the late phase of angiogram.

Figure 4

Electroretinography and S-Cone ERG findings in case 2. A: ERG findings in case 2. ERG shows severely reduced rod specific responses, response to standard flash was delayed with low amplitude waveform under photopic and scotopic conditions, the 30 Hz flicker was delayed and of lower amplitude. B: S-Cone ERG with blue flash and orange background showing abnormally large, delayed, simplified waveform as enhanced S cone ERG responses.

Figure 5

Chromatogram representing the p.Asp406Gly mutation in the NR2E3 gene. A: p.Asp406Gly mutation in the homozygous state. B: p.Asp406Gly mutation in the heterozygous state. C: Wild type. The underline marks the mutated codon. The arrow indicates the position of the mutation.

Figure 6

Evolutionary conservation of p.Asp406Gly (D406G) mutation in different species. Amino acid residues highly conserved in all species are indicated by asterisk, and lower identity are shown using colon. Red color box indicate NR2E3 mutations analyzed in this study.