Disruption of the retinitis pigmentosa 28 gene Fam161a in mice affects photoreceptor ciliary structure and leads to progressive retinal degeneration

Hum Mol Genet. 2014 Oct 1;23(19):5197-210. doi: 10.1093/hmg/ddu242. Epub 2014 May 15.


Mutations in the FAM161A gene were previously identified as the cause for autosomal-recessive retinitis pigmentosa 28. To study the effects of Fam161a dysfunction in vivo, we generated gene-trapped Fam161a(GT/GT) mice with a disruption of its C-terminal domain essential for protein-protein interactions. We confirmed the absence of the full-length Fam161a protein in the retina of Fam161a(GT/GT) mice using western blots and showed weak expression of a truncated Fam161a protein by immunohistochemistry. Histological analyses demonstrated that photoreceptor segments were disorganized in young Fam161a(GT/GT) mice and that the outer retina was completely lost at 6 months of age. Reactive microglia appeared in the outer retina and electroretinography showed an early loss of photoreceptor function in 4-month-old Fam161a(GT/GT) animals. Light and electron microscopy revealed a remarkable phenotype of a significantly shortened connecting cilium, spread ciliary microtubule doublets and disturbed disk organization in Fam161a(GT/GT) photoreceptor cells. Co-immunolabeling experiments demonstrated reduced expression and mislocalization of centrin 3 and disturbed targeting of the Fam161a interactors lebercilin and Cep290, which were restricted to the basal body and proximal connecting cilium in Fam161a(GT/GT) retinas. Moreover, we identified misrouting of the outer segment cargo proteins opsin and rds/peripherin 2 in Fam161a(GT/GT) mice. In conclusion, our results suggest a critical role for the C-terminal domain of Fam161a for molecular interactions and integrity of the connecting cilium. Fam161a is required for the molecular delivery into the outer segment cilium, a function which is essential for outer segment disk formation and ultimately visual function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Carrier Proteins / metabolism
  • Eye Proteins / genetics*
  • Female
  • Gene Expression
  • Gene Targeting
  • Genetic Loci
  • Genotype
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Microglia / metabolism
  • Mutation*
  • Photoreceptor Cells / metabolism*
  • Photoreceptor Cells / pathology*
  • Photoreceptor Cells / ultrastructure
  • Protein Binding
  • Protein Transport
  • Retina / metabolism
  • Retinal Degeneration / genetics*
  • Retinal Degeneration / pathology
  • Retinal Degeneration / physiopathology
  • Retinal Pigment Epithelium / metabolism
  • Retinal Pigment Epithelium / pathology
  • Vision Disorders / genetics
  • Vision Disorders / pathology
  • Vision Disorders / physiopathology


  • Carrier Proteins
  • Eye Proteins
  • Fam161A protein, mouse