Retinopathy mutations in the bZIP protein NRL alter phosphorylation and transcriptional activity

Atsuhiro Kanda, James S. Friedman, Koji M. Nishiguchi, Anand Swaroop

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)


The transcription factor neural retina leucine zipper (NRL) is required for rod photoreceptor differentiation during mammalian retinal development. NRL interacts with CRX, NR2E3, and other transcription factors and synergistically regulates the activity of photoreceptor-specific genes. Mutations in the human NRL gene are associated with retinal degenerative diseases. Here we report functional analyses of 17 amino acid variations and/or mutations of NRL. We show that 13 of these lead to changes in NRL phosphorylation. Six mutations at residues p.S50 (c.148T>A, c.148T>C, and c.149C>T) and p.P51 (c.151C>A, c.151C>T, and c.152C>T), identified in patients with autosomal dominant retinitis pigmentosa, result in a major NRL isoform that exhibits reduced phosphorylation but enhanced activation of the rhodopsin promoter. The truncated NRL mutant proteins - p.L75fs (c.224_225insC) and p.L160fs (c.459_477dup) - do not localize to the nucleus because of the absence of bZIP domain. The p.L160P (c.479T>C), p.L160fs, and p.R218fs (c.654delC) mutant proteins do not bind to the NRL-response element, as revealed by electrophoretic mobility shift assays. These three and p.S225N (c.674G>A) mutant show reduced transcriptional activity and may contribute to recessive disease. The p.P67S (c.199C>T) and p.L235F (c.703C>T) variations in NRL do not appear to directly cause retinitis pigmentosa, while p.E63K (c.187G>A), p.A76V (c.227C>T), p.G122E (c.365G>A), and p.H125Q (c.375C>G) are of uncertain significance. Our results support the notion that gain-of-function mutations in the NRL gene cause autosomal dominant retinitis pigmentosa while loss-of-function NRL mutations lead to autosomal recessive retinitis pigmentosa. We propose that differential phosphorylation of NRL fine-tunes its transcriptional regulatory activity, leading to a more precise control of gene expression.

Original languageEnglish
Pages (from-to)589-598
Number of pages10
JournalHuman mutation
Issue number6
Publication statusPublished - 2007 Jun
Externally publishedYes


  • DNA binding
  • Gene expression
  • Gene regulation
  • NRL
  • Neural retina leucine zipper
  • Phosphorylation
  • Photoreceptor
  • Retinal degeneration
  • Retinal development
  • Rhodopsin
  • Transcription factor

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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