NR2E3 – Goldmann-Favre Syndrome

NR2E3 is an orphan nuclear receptor whose biallelic variants cause Goldmann-Favre syndrome (GFS), an autosomal recessive retinal dystrophy characterized by night blindness, retinal disorganization, and cone preservation in the macula. The association between NR2E3 and Goldmann-Favre syndrome is supported by multiple independent clinical reports and mechanistic studies.

Four unrelated GFS probands have been reported with NR2E3 variants. Histopathology of an 88-year-old male with a homozygous c.119-2A>C splice variant demonstrated near-complete rod loss, cone rosettes, and disrupted retinal lamination (PMID:19852574). A three-generation family segregated a novel homozygous c.1117A>G (p.Asp406Gly) variant in affected members and heterozygous carriage in unaffected relatives, confirming autosomal recessive inheritance (PMID:24891813). A 64-year-old woman with Coats-like exudative vitreoretinopathy and cystoid macular edema harbored homozygous c.932G>A (p.Arg311Gln) consistent with GFS (PMID:35243140). Additionally, a cohort study identified one GFS patient among NR2E3 mutation carriers in 11 unrelated cases of enhanced S-cone syndrome, GFS, and clumped pigmentary retinal degeneration (PMID:12963616).

Segregation in the 2014 family demonstrated cosegregation of homozygous variants with disease across three generations, supporting pathogenicity. The variant spectrum includes two missense changes (p.Asp406Gly, p.Arg311Gln) and a canonical splice-site mutation, with p.Arg311Gln representing a recurrent allele in multiple cohorts. Carrier frequency and population data remain limited for GFS-specific alleles.

Functional studies reveal that loss of NR2E3 activity disrupts rod differentiation and derepresses cone gene expression. Histological analysis of an affected human retina showed absent rods and mislocalized cone opsins, while the rd7 mouse model (a natural L1 insertion in Nr2e3) recapitulates enhanced S-cone and GFS-like phenotypes, confirming concordant mechanisms of photoreceptor dysregulation (PMID:16723373).

Collectively, genetic and experimental evidence support a loss-of-function mechanism for NR2E3 in GFS, where impaired transcriptional repression of cone-specific genes and failure of rod development underlie pathology. No conflicting evidence has been reported specific to GFS.

Key Take-home: NR2E3-associated Goldmann-Favre syndrome is an autosomal recessive photoreceptor dystrophy with characteristic histopathology and rod-cone phenotypes; molecular testing for NR2E3 variants facilitates definitive diagnosis and genetic counseling.

References

• Ophthalmic Genetics • 2009 • Retinal pathology of a patient with Goldmann-Favre syndrome. PMID:19852574
• Molecular Vision • 2014 • A novel mutation in the NR2E3 gene associated with Goldmann-Favre syndrome and vasoproliferative tumor of the retina. PMID:24891813
• American Journal of Ophthalmology Case Reports • 2022 • Multimodal treatment of Coats-like exudative vitreoretinopathy in Goldmann-Favre syndrome. PMID:35243140
• Archives of Ophthalmology • 2003 • Shared mutations in NR2E3 in enhanced S-cone syndrome, Goldmann-Favre syndrome, and many cases of clumped pigmentary retinal degeneration. PMID:12963616
• Human Molecular Genetics • 2006 • Effects of L1 retrotransposon insertion on transcript processing, localization and accumulation: lessons from the retinal degeneration 7 mouse and implications for the genomic ecology of L1 elements. PMID:16723373

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