Mutation analysis ofNR2E3 andNRL genes in Enhanced S Cone Syndrome

Abstract

Ten new and seventeen previously reported Enhanced S Cone Syndrome (ESCS) subjects were used to search for genetic heterogeneity. All subjects were diagnosed with ESCS on the basis of clinical, psychophysical and/or electroretinography testing using published criteria. Mutation analysis was performed on the NR2E3 nuclear receptor gene by single strand conformation analysis and direct sequencing, which revealed either homozygous (N=13) or compound heterozygous (N=11) mutations in 24 subjects (89%), heterozygous mutations in 2 subjects (7%) and no mutations in 1 subject (4%). Fifteen different mutations were identified, including six not previously reported. The subject (Patient A) with no detected NR2E3 mutation had features not usually associated with ESCS, in particular moderate rod photoreceptor function in peripheral retina and an abnormally thick retinal nerve fibre layer. Mutation analysis of the NRL, CRX, NR1D1 and THRB genes in this individual revealed a heterozygous one base-pair insertion in exon 2 of the NRL gene, which results in a predicted truncation of the NRL protein. Loss-of-function NRL alleles have not been described previously in humans, but since the same mutation was present in unaffected family members, it raises the possibility that the abnormal ESCS phenotype in Patient A may result from a digenic mechanism, with a heterozygous NRL mutation and a mutation in another unknown gene.

NR2E3mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP)

“…No NR2E3 mutations were detected in seven ESCS patients [Audo et al, 2008;Bandah et al, 2009;Haider et al, 2000;Khan et al, 2007;Wright et al, 2004] and in about 50% of the CRPD patients [Sharon et al, 2003]. Sequencing of the NRL gene detected a heterozygous mutation in one ESCS patient , and one family affected by CRPD [Nishiguchi et al, 2004].…”

“…Strikingly, homozygous carriers of the p.R311Q mutation have been diagnosed with ESCS [Bernal et al, 2008;Haider et al, 2000;Iannaccone et al, 2009;Khan et al, 2007;Nakamura et al, 2002;Wright et al, 2004], GFS [Bernal et al, 2008;Chavala et al, 2005;Pachydaki et al, 2009], CPRD [Sharon et al, 2003], and arRP [Bandah et al, 2009;Gerber et al, 2000]. The original cohort of patients diagnosed with arRP was not available for ERG analyses, but the reported clinical data was very similar to ESCS [Gerber et al, 2000;Weleber, 2002].…”

Genotype–phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing

“…However, a pathogenic homozygous mutation in the NR2E3 gene (c.290G>A, p.R97H) was identified (Supplementary Figure S1 online) that was reported to cause enhanced S cone syndrome (ESCS) in previous studies. 20,21 To explain this inconsistency, proband W29-1 was sent for a clinical reassessment. Full-field electroretinography showed extinguished rod responses (Supplementary Figure S1 online).…”

“…Electroretinography demonstrated that the phenotype was consistent with typical ESCS. 20,21 Consequently, we successfully revised the clinical diagnosis of patient W29-1. To the best of our knowledge, this is the first recorded case of ESCS in the Chinese population.…”

Regulation of photoreceptor gene expression by Crx-associated transcription factor network

“…Human genetic studies: Mutations in human NR2E3 cause enhanced S-cone syndrome (ESCS), an autosomal recessive disease featuring hyperfunction of blue cones, defective function of rods, and blindness in the late stages (Haider et al, 2000;Jacobson et al, 2004;Wright et al, 2004). Histopathological studies showed excess S-cones in the retina, some of which express both S-and M-cone opsins (Milam et al, 2002), which is unusual in humans (Lukats et al, 2005;Peichl, 2005).…”