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An Arg311Gln NR2E3 mutation in a family with classic Goldmann-Favre syndrome
  1. S H Chavala*,
  2. A Sari*,
  3. H Lewis,
  4. G J T Pauer,
  5. E Simpson,
  6. S A Hagstrom,
  7. E I Traboulsi
  1. Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
  1. Correspondence to: Elias I Traboulsi MD, Cole Eye Institute, The Cleveland Clinic Foundation, Desk i-32, 9500 Euclid Avenue, Cleveland, OH 44195, USA;

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Goldmann-Favre syndrome (GFS) is one of the rarest inherited vitreoretinal dystrophies that manifests with hemeralopia, degenerative vitreous changes, peripheral and central retinoschisis, a liquefied vitreous cavity with preretinal band-shaped structures, macular oedema, cataract formation, and an abnormal electroretinogram (ERG).1–3 The term “clumped pigmentary retinal degeneration” (CPRD) describes a group of patients with decreased night and peripheral vision who have round and irregular clumps of pigment in the mid-peripheral fundus with little or no evidence of bone spicule formation.4 This pattern of pigmentation occurs in retinitis pigmentosa (RP) with preserved para-arteriolar retinal pigment epithelium (PPRPE),5 enhanced S-cone syndrome (ESCS), and GFS, and these disorders share common mutations in the NR2E3 gene, which is involved in retinal cell fate determination.6

We present clinical and molecular genetic studies of a family from the United Arab Emirates with a classic GFS phenotype and a mutation in the NR2E3 gene.

Case reports

Two affected siblings and two unaffected siblings from a consanguineous family in which there were nine unaffected siblings were examined. GFS was diagnosed according to previous clinical descriptions of the disease.1,2 Complete ocular examinations, fluorescein angiography (FA), ERG, and optical coherence tomography (OCT) were done. ERGs were performed according to ISCEV recommendations.7

Blood samples were obtained to study the NR2E3 gene after informed consent was secured following explanation of the procedures; all studies conformed to the standards of the institutional review board at the Cleveland Clinic Foundation and the Declaration of Helsinki.

DNA was extracted from leucocytes and the coding exons of the NR2E3 gene were amplified using polymerase chain reaction (PCR) with published primers and methodology.4,8 Sequencing was accomplished using an automated sequencing unit (Beckman-Colter, CEQ 2000).

Case 1 had a best corrected visual acuity of 20/200 right eye with +0.25+0.50×135 and 20/400 left eye with +1.00 sphere, and case 2 had a best corrected visual acuity 20/60 right eye with −3.75+2.25×080 and 20/50 left eye with −2.75+2.75×085. External ocular examination, pupillary reaction, applanation tonometry, and slit lamp biomicroscopy were within normal limits. Both patients had macular schisis and yellowish lesions, some with pigmented edges, deep to the neurosensory retina in both eyes (fig 1A and 1B). Both patients had prominent macular oedema in both eyes detected on FA and OCT (fig 1C and 1D). ERGs obtained to low intensity stimuli presented to the dark adapted eye were not different from the baseline. When a high intensity stimulus flash was used, large amplitude ERGs were obtained (fig 2). These responses had an abnormally slow waveform. Unlike control subjects, the presence of a steady adapting field had a modest effect on ERG amplitude and almost no effect on ERG waveform in the two patients. Flicker ERGs were also slower than control.

Figure 1

 (A) Posterior pole photograph of case 1’s right eye reveals macular retinoschisis, subretinal whitish band-like lesions, and round clumps of pigment. (B) Fundus photograph of case 1’s right eye demonstrates yellow lesions deep to the retina with nummular areas of clumped pigment. (C) OCT image of case 1’s right eye shows multiple, large cystic spaces in the neurosensory retina of the macula. (D) OCT image of case 1’s left eye shows multiple macular schisis cavities in the neurosensory retina.

Figure 2

 ERGs recorded from a normal control subject (left) and from patients N A-K (case 1, middle) and A A-K (case 2, right). Different rows indicate different stimulus conditions: top row, dark adapted ERG recorded to −2.0 log cd s/m2 stimulus; second row, dark adapted ERG recorded to 0.5 log cd s/m2 stimulus; third row, light adapted ERG recorded to 0.5 log cd s/m2 stimulus; fourth row, 31 Hz flicker ERG recorded to 0.5 log cd s/m2 stimulus. Vertical bars indicate time of flash presentation. For both patients, the responses obtained from the two eyes are superimposed.

Both patients were homozygous for a point mutation 932 G>A in exon 6, leading to an Arg311Gln change in the NR2E3 protein (fig 3). One of the unaffected siblings carried one mutant allele and the other was not a carrier.

Figure 3

 G→A mutation changes amino acid 311 from Arg to Gln. Sequences are shown from homozygous patient (top), heterozygous carrier (middle), and normal control (bottom).


NR2E3 encodes a retinal nuclear receptor and is part of a large family of nuclear receptor transcription factors involved in signaling pathways for photoreceptors.9 This retinal nuclear receptor, limited to the outer nuclear layer of the human retina, has been shown to regulate pathways involved in embryonic development,8,10 as well as maintain proper cell function in adults.9 The homozygous mutation, Arg311Gln, in exon 6 of the NR2E3 gene causes ESCS, CPRD, and RP by previous reports.4,8,11 Sharon et al reviewed the literature and found that exon 6 is where most disease mutations are found. The mechanism for the phenotypic variability associated with the Arg311Gln mutation is unclear but NR2E3 appears to have a role in determining photoreceptor phenotype.6

Mutations in NR2E3 result in retinal disorganisation12 as a result of defective development, known as S-cone fragility, or abnormal maintenance of mature photoreceptors.8,10,13 This abnormal retinal architecture is evidenced phenotypically as macular retinoschisis, as in GFS. From a clinical perspective, OCT testing in our patients has provided information about the location of retinoschisis typically found in the neurosensory retina in GFS and supports one previous report.14 Our study corroborates previous reports that the classic GFS phenotype results from mutations in the NR2E3 gene, and that the combination of night blindness and clumped retinal pigment deposits should raise suspicion that a patient may a have a mutation in the NR2E3 gene.


Supported by NEI Core Grant R24 EY15638. We thank Neal Peachey for comment on the manuscript and assistance in preparing the ERG figure.



  • * These two authors contributed equally to the study.The authors have no relevant financial interest in this article.

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