Homozygosity for a Recessive Loss-of-Function Mutation of the NRL Gene Is Associated With a Variant of Enhanced S-Cone Syndrome

Abstract

Citation: Newman H, Blumen SC, Braverman I, et al. Homozygosity for a recessive loss-of-function mutation of the NRL gene is associated with a variant of enhanced S-cone syndrome. Invest Ophthalmol Vis Sci. 2016;57:5361-5371. DOI:10.1167/ iovs.16-19505 PURPOSE. To investigate the genetic basis for severe visual complaints by Bukharan Jewish patients with oculopharyngeal muscular dystrophy (OPMD). METHODS.Polymerase chain reaction amplification and direct sequencing were used to test for NRL, PABPN1, and NR2E3 mutations. Complete ophthalmic examination included bestcorrected visual acuity, biomicroscopic examination, optical coherence tomography, and fundus autofluorescence. Detailed electroretinography (ERG) testing was conducted including expanded International Society for Clinical Electrophysiology of Vision protocol for light-adapted and dark-adapted conditions, measurements of S-cone function, and ON-OFF light-adapted ERG.RESULTS. The index patients were homozygotes for both a dominant mutation of the PABPN1 gene, (GCN)13, and a recessive mutation of the NRL gene, p.R31X, on chromosome 14q11.1, leading to early-onset OPMD accompanied by night blindness and reduced visual acuity. No mutations were found in the NR2E3 gene. Both patients were of Bukharan Jewish origin, but from unrelated families. Electroretinography responses of both patients were dominated by short-wavelength-sensitive mechanisms, with no detectable rod function, similar to the ERG responses of individuals with enhanced S-cone syndrome (ESCS) due to NR2E3 mutations. Heterozygotes for the PABPN1 and NRL mutations demonstrated normal fundi and ERG responses.CONCLUSIONS. Homozygosity for the recessive NRL mutation described here appears to be associated with a distinct retinal phenotype, demonstrating ERG characteristics similar to those of ESCS patients. This report expands the spectrum of NRL recessive mutations, as well as the genetic spectrum of ESCS, and indicates a new syndrome of OPMD with an ESCS-like phenotype.

Human S-cone electroretinograms obtained by silent substitution stimulation

“…The S-cone ERG recorded from the participant with ESCS using the triple silent substitution stimulus also appears to exhibit morphological features consistent with those that have been previously described for this condition [e.g. 51,52,69]. ESCS is a rare inherited degenerative retinal condition that, in addition to other retinal changes, is associated with increased S-cone sensitivity [45] resulting from an increased number of S-cones in the retina compared to normals [42][43][44].…”

Generation of a rod-specific NRL reporter line in human pluripotent stem cells

“…This targeted knock-in strategy is also novel among mammalian rod reporter lines, since the widely used Nrl -GFP mouse was created by inserting multiple copies of an Nrl-GFP transgene randomly in the murine genome 1 . While our approach does create a nonfunctional NRL allele, no phenotypic consequences are observed in human patients heterozygous for NRL loss of function mutations 29 , 30 .…”

Retinogenesis of the Human Fetal Retina: An Apical Polarity Perspective

“…Several retinal TFs including Otx2, Crx, Nrl, and Nr2e3 control rod and cone-specific photoreceptor specification. Mutations in Crx can cause Leber congenital amaurosis (LCA), cone-rod dystrophy (CRD), and Retinitis pigmentosa (RP), while Nrl and Nr2e3 mutations can cause RP and enhanced S-cone syndrome [92][93][94][95][96][97][98]. Otx2 can determine both rod and cone photoreceptor cell fate, while Crx acts with Nrl and Rorβ for terminal photoreceptor gene expression controlling the cone/rod ratio [99][100][101][102].…”