Spata7 is a retinal ciliopathy gene critical for correct RPGRIP1 localization and protein trafficking in the retina

Hum Mol Genet. 2015 Mar 15;24(6):1584-601. doi: 10.1093/hmg/ddu573. Epub 2014 Nov 14.

Abstract

Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) are severe hereditary diseases that causes visual impairment in infants and children. SPATA7 has recently been identified as the LCA3 and juvenile RP gene in humans, whose function in the retina remains elusive. Here, we show that SPATA7 localizes at the primary cilium of cells and at the connecting cilium (CC) of photoreceptor cells, indicating that SPATA7 is a ciliary protein. In addition, SPATA7 directly interacts with the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1), a key connecting cilium protein that has also been linked to LCA. In the retina of Spata7 null mutant mice, a substantial reduction of RPGRIP1 levels at the CC of photoreceptor cells is observed, suggesting that SPATA7 is required for the stable assembly and localization of the ciliary RPGRIP1 protein complex. Furthermore, our results pinpoint a role of this complex in protein trafficking across the CC to the outer segments, as we identified that rhodopsin accumulates in the inner segments and around the nucleus of photoreceptors. This accumulation then likely triggers the apoptosis of rod photoreceptors that was observed. Loss of Spata7 function in mice indeed results in a juvenile RP-like phenotype, characterized by progressive degeneration of photoreceptor cells and a strongly decreased light response. Together, these results indicate that SPATA7 functions as a key member of a retinal ciliopathy-associated protein complex, and that apoptosis of rod photoreceptor cells triggered by protein mislocalization is likely the mechanism of disease progression in LCA3/ juvenile RP patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cattle
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Deletion
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Photoreceptor Connecting Cilium / metabolism
  • Photoreceptor Connecting Cilium / pathology*
  • Protein Transport
  • Proteins / metabolism*
  • Retinal Cone Photoreceptor Cells / pathology
  • Retinal Rod Photoreceptor Cells / metabolism
  • Retinal Rod Photoreceptor Cells / pathology*
  • Rhodopsin / metabolism

Substances

  • DNA-Binding Proteins
  • Proteins
  • RPGRIP1 protein, human
  • SPATA7 protein, human
  • Rhodopsin