REEP6 deficiency impairs ER and Golgi morphologies and causes retinal degeneration by attenuating the expression of phototransduction proteins

REEP proteins, belonging to the YIP superfamily, are membrane proteins involved in regulating membrane curvature. Mutations in human REEP6 are associated with Retinitis pigmentosa (RP), a blinding disorder modelled by mice lacking REEP6. The phenotype was recently attributed to abnormal trafficking of PDE6 and absence of guanylate cyclases (GCs) in photoreceptors, presumably caused by ER dysfunction. Here, we generated an independent and novel Reep6 knockout mouse model based on deletion of exons 2-5. Our Reep6 -deficient mouse line showed progressive retinal degeneration, but in contrast to a previous report exhibited normal trafficking of PDE6. Reep6 -/- expression levels of PDE6, GCs, rhodopsin and rhodopsin kinase (GRK1) were reduced at P30. Attenuated expression of membrane proteins may stem from abnormal ER and Golgi function, as in vitro expression of REEP6 altered the ER marker and Golgi morphologies. Additionally, RNA-seq revealed that deletion of REEP6 caused reduced expression of multiple phototransduction proteins at the transcription level and activated the inflammation pathway. GNB2 was the only protein whose transcription was upregulated in the KO. Thus, retinal degeneration associated with REEP6 mutations is the consequence of reduced expression of rod phototransduction proteins presumably mediated by ER and Golgi dysfunction.