Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa

Am J Hum Genet. 2016 Dec 1;99(6):1305-1315. doi: 10.1016/j.ajhg.2016.10.008. Epub 2016 Nov 23.


Retinitis pigmentosa (RP) is the most frequent form of inherited retinal dystrophy. RP is genetically heterogeneous and the genes identified to date encode proteins involved in a wide range of functional pathways, including photoreceptor development, phototransduction, the retinoid cycle, cilia, and outer segment development. Here we report the identification of biallelic mutations in Receptor Expression Enhancer Protein 6 (REEP6) in seven individuals with autosomal-recessive RP from five unrelated families. REEP6 is a member of the REEP/Yop1 family of proteins that influence the structure of the endoplasmic reticulum but is relatively unstudied. The six variants identified include three frameshift variants, two missense variants, and a genomic rearrangement that disrupts exon 1. Human 3D organoid optic cups were used to investigate REEP6 expression and confirmed the expression of a retina-specific isoform REEP6.1, which is specifically affected by one of the frameshift mutations. Expression of the two missense variants (c.383C>T [p.Pro128Leu] and c.404T>C [p.Leu135Pro]) and the REEP6.1 frameshift mutant in cultured cells suggest that these changes destabilize the protein. Furthermore, CRISPR-Cas9-mediated gene editing was used to produce Reep6 knock-in mice with the p.Leu135Pro RP-associated variant identified in one RP-affected individual. The homozygous knock-in mice mimic the clinical phenotypes of RP, including progressive photoreceptor degeneration and dysfunction of the rod photoreceptors. Therefore, our study implicates REEP6 in retinal homeostasis and highlights a pathway previously uncharacterized in retinal dystrophy.

MeSH terms

  • Adolescent
  • Alleles
  • Animals
  • Child
  • Child, Preschool
  • Eye Proteins / chemistry
  • Eye Proteins / genetics*
  • Eye Proteins / metabolism
  • Female
  • Genes, Recessive / genetics*
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Male
  • Membrane Proteins
  • Membrane Transport Proteins / genetics*
  • Mice
  • Mutation / genetics*
  • Mutation, Missense / genetics
  • Phenotype
  • Photoreceptor Cells, Vertebrate / cytology
  • Photoreceptor Cells, Vertebrate / metabolism
  • Retinitis Pigmentosa / genetics*
  • Young Adult


  • Eye Proteins
  • Membrane Proteins
  • Membrane Transport Proteins
  • REEP6 protein, human
  • REEP6 protein, mouse