期刊
HUMAN MOLECULAR GENETICS
卷 23, 期 19, 页码 5197-5210出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddu242
关键词
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资金
- Deutsche Forschungsgemeinschaft (DFG) [LA1203/8-1, GRK 1044]
- ProRetina Stiftung
- FAUN-Stiftung
- European Community [FP7/2009/241955, FP7/2009/242013]
- BMBF [0314106]
- ERA-Net for Research on Rare Diseases (EUR-USH)
- Hans und Marlies Stock-Stiftung
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 fulllength Fam161a protein in the retina of Fam161a(GTIGT) 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(GTIGT) 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. Fam 161a 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.
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