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AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis

Abstract

Degeneration of photoreceptors is a common feature of ciliopathies, owing to the importance of the specialized ciliary structure of these cells. Mutations in AHI1, which encodes a cilium-localized protein, have been shown to cause a form of Joubert syndrome that is highly penetrant for retinal degeneration1,2. We show that Ahi1-null mice fail to form retinal outer segments and have abnormal distribution of opsin throughout their photoreceptors. Apoptotic cell death of photoreceptors occurs rapidly between 2 and 4 weeks of age in these mice and is significantly (P = 0.00175 and 0.00613) delayed by a reduced dosage of opsin. This phenotype also shows dosage-sensitive genetic interactions with Nphp1, another ciliopathy-related gene. Although it is not a primary cause of retinal blindness in humans, we show that an allele of AHI1 is associated with a more than sevenfold increase in relative risk of retinal degeneration within a cohort of individuals with the hereditary kidney disease nephronophthisis. Our data support context-specific roles for AHI1 as a contributor to retinopathy and show that AHI1 may explain a proportion of the variability in retinal phenotypes observed in nephronophthisis.

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Figure 1: Degeneration of photoreceptor cells following failed outer segment development in Ahi1−/− mouse retina.
Figure 2: Opsin accumulation in Ahi1−/− photoreceptors.
Figure 3: Opsin contributes to cell death in Ahi1−/− mice.
Figure 4: Genetic interaction of Ahi1 with Nphp1.

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References

  1. Valente, E.M. et al. AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders. Ann. Neurol. 59, 527–534 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Parisi, M.A. et al. AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome. J. Med. Genet. 43, 334–339 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Quinlan, R.J., Tobin, J.L. & Beales, P.L. Modeling ciliopathies: primary cilia in development and disease. Curr. Top. Dev. Biol. 84, 249–310 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Dixon-Salazar, T. et al. Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria. Am. J. Hum. Genet. 75, 979–987 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ferland, R.J. et al. Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat. Genet. 36, 1008–1013 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Jiang, X., Hanna, Z., Kaouass, M., Girard, L. & Jolicoeur, P. Ahi-1, a novel gene encoding a modular protein with WD40-repeat and SH3 domains, is targeted by the Ahi-1 and Mis-2 provirus integrations. J. Virol. 76, 9046–9059 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Eley, L. et al. Jouberin localizes to collecting ducts and interacts with nephrocystin-1. Kidney Int. 74, 1139–1149 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Hildebrandt, F. et al. A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nat. Genet. 17, 149–153 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Konrad, M. et al. Large homozygous deletions of the 2q13 region are a major cause of juvenile nephronophthisis. Hum. Mol. Genet. 5, 367–371 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Higginbotham, H., Bielas, S., Tanaka, T. & Gleeson, J.G. Transgenic mouse line with green-fluorescent protein-labeled Centrin 2 allows visualization of the centrosome in living cells. Transgenic Res. 13, 155–164 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Wolfrum, U. & Salisbury, J.L. Expression of centrin isoforms in the mammalian retina. Exp. Cell Res. 242, 10–17 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Pazour, G.J. et al. The intraflagellar transport protein, IFT88, is essential for vertebrate photoreceptor assembly and maintenance. J. Cell Biol. 157, 103–113 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fliegauf, M. et al. Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia. J. Am. Soc. Nephrol. 17, 2424–2433 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Humphries, M.M. et al. Retinopathy induced in mice by targeted disruption of the rhodopsin gene. Nat. Genet. 15, 216–219 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Lem, J. et al. Morphological, physiological, and biochemical changes in rhodopsin knockout mice. Proc. Natl. Acad. Sci. USA 96, 736–741 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gross, A.K. et al. Defective development of photoreceptor membranes in a mouse model of recessive retinal degeneration. Vision Res. 46, 4510–4518 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Burns, M.E. & Arshavsky, V.Y. Beyond counting photons: trials and trends in vertebrate visual transduction. Neuron 48, 387–401 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Marszalek, J.R. et al. Genetic evidence for selective transport of opsin and arrestin by kinesin-II in mammalian photoreceptors. Cell 102, 175–187 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Deretic, D. A role for rhodopsin in a signal transduction cascade that regulates membrane trafficking and photoreceptor polarity. Vision Res. 46, 4427–4433 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Bhowmick, R. et al. Photoreceptor IFT complexes containing chaperones, guanylyl cyclase 1 and rhodopsin. Traffic 10, 648–663 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Matsuda, T. & Cepko, C.L. Electroporation and RNA interference in the rodent retina in vivo and in vitro. Proc. Natl. Acad. Sci. USA 101, 16–22 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Matsuda, T. & Cepko, C.L. Controlled expression of transgenes introduced by in vivo electroporation. Proc. Natl. Acad. Sci. USA 104, 1027–1032 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Davenport, J.R. et al. Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Curr. Biol. 17, 1586–1594 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. den Hollander, A.I., Roepman, R., Koenekoop, R.K. & Cremers, F.P. Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog. Retin. Eye Res. 27, 391–419 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Liang, Y. et al. Rhodopsin signaling and organization in heterozygote rhodopsin knockout mice. J. Biol. Chem. 279, 48189–48196 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Jiang, S.T. et al. Essential role of nephrocystin in photoreceptor intraflagellar transport in mouse. Hum. Mol. Genet. 18, 1566–1577 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Marquardt, T. et al. Pax6 is required for the multipotent state of retinal progenitor cells. Cell 105, 43–55 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Sunyaev, S. et al. Prediction of deleterious human alleles. Hum. Mol. Genet. 10, 591–597 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Yue, P., Melamud, E. & Moult, J. SNPs3D: candidate gene and SNP selection for association studies. BMC Bioinformatics 7, 166 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Sung, C.H., Schneider, B.G., Agarwal, N., Papermaster, D.S. & Nathans, J. Functional heterogeneity of mutant rhodopsins responsible for autosomal dominant retinitis pigmentosa. Proc. Natl. Acad. Sci. USA 88, 8840–8844 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tory, K. et al. High NPHP1 and NPHP6 mutation rate in patients with Joubert syndrome and nephronophthisis: potential epistatic effect of NPHP6 and AHI1 mutations in patients with NPHP1 mutations. J. Am. Soc. Nephrol. 18, 1566–1575 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Kroes, H.Y. et al. DNA analysis of AHI1, NPHP1 and CYCLIN D1 in Joubert syndrome patients from the Netherlands. Eur. J. Med. Genet. 51, 24–34 (2008).

    Article  PubMed  Google Scholar 

  33. Caridi, G. et al. Renal-retinal syndromes: association of retinal anomalies and recessive nephronophthisis in patients with homozygous deletion of the NPH1 locus. Am. J. Kidney Dis. 32, 1059–1062 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Spielman, R.S., McGinnis, R.E. & Ewens, W.J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J. Hum. Genet. 52, 506–516 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Hsiao, Y.C. et al. Ahi1, whose human ortholog is mutated in Joubert syndrome, is required for Rab8a localization, ciliogenesis and vesicle trafficking. Hum. Mol. Genet. 18, 3926–3941 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Khanna, H. et al. A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies. Nat. Genet. 41, 739–745 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Caridi, G. et al. Nephronophthisis type 1 deletion syndrome with neurological symptoms: prevalence and significance of the association. Kidney Int. 70, 1342–1347 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Koizumi, H., Tanaka, T. & Gleeson, J.G. Doublecortin-like kinase functions with doublecortin to mediate fiber tract decussation and neuronal migration. Neuron 49, 55–66 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Hooper, M., Hardy, K., Handyside, A., Hunter, S. & Monk, M. HPRT-deficient (Lesch-Nyhan) mouse embryos derived from germline colonization by cultured cells. Nature 326, 292–295 (1987).

    Article  CAS  PubMed  Google Scholar 

  40. Lakso, M. et al. Efficient in vivo manipulation of mouse genomic sequences at the zygote stage. Proc. Natl. Acad. Sci. USA 93, 5860–5865 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tronche, F. et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat. Genet. 23, 99–103 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. El Bradey, M. et al. Preventive versus treatment effect of AG3340, a potent matrix metalloproteinase inhibitor in a rat model of choroidal neovascularization. J. Ocul. Pharmacol. Ther. 20, 217–236 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Lancaster, M.A. et al. Impaired Wnt-β-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathy. Nat. Med. 15, 1046–1054 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hong, D.H. et al. RPGR isoforms in photoreceptor connecting cilia and the transitional zone of motile cilia. Invest. Ophthalmol. Vis. Sci. 44, 2413–2421 (2003).

    Article  PubMed  Google Scholar 

  45. Liu, Q. et al. Identification and subcellular localization of the RP1 protein in human and mouse photoreceptors. Invest. Ophthalmol. Vis. Sci. 43, 22–32 (2002).

    PubMed  Google Scholar 

  46. Fleiss, J.L., Levin, B.A. & Paik, M.C. Statistical Methods for Rates and Proportions (Wiley, 2003).

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Acknowledgements

We thank K. Siever and K. Teofilo for assistance with histology; G. Silva, L. Cheng and M. Davidson for assistance with ERG testing; A. Avila for assistance with clinical data and selecting controls; J. Lem, G. Lemke, T. Burstyn-Cohen and A. Wynshaw-Boris for sharing mice and for feedback and suggestions; K. Zhang, L. Goldstein and B. Zheng for feedback and suggestions; T. Li and E. Pierce for sharing antibodies; C.-H. Sung for sharing rhodopsin plasmid; J. Kim and V. Cantagrel for technical advice; and J. Meerloo with the University of California at San Diego (UCSD) Neurosciences Microscopy Shared Facility (NINDS P30NS047101) for microscopy services and support. This work was supported by the US National Institutes of Health R01NS048453 (J.G.G.), R01DK068306 (F.H.), P30NS047101 (J.G.G.), F31NS059281 (C.M.L.), R01EY007042 (D.S.W.), UCSD Genetics Training Program institutional training grant T32 GM008666 from the National Institute for General Medical Sciences (C.M.L. and M.A.L), GP08145 grant from Telethon-Italy (E.M.V.) and the Burroughs Wellcome Fund (J.G.G.). D.S.W. is a Jules and Doris Stein RPB Professor. J.G.G. and F.H. are investigators of the Howard Hughes Medical Institute.

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Contributions

C.M.L and J.G.G. designed the study and experiments with substantial contributions from D.S.W. C.M.L., A.K., F.H. and M.L. developed mutant mice and C.M.L., E.A.O., F.H., H.-J.G. and J.F.O. performed initial characterization. C.M.L. performed mouse experiments. V.S.L. performed electron microscopy. G.C., E.M.V., G.M.G. and B.D. ascertained and supervised genotyping of affected persons and contributed to analysis. A.I.d.H., R.K.K. and F.P.M.C. contributed LCA samples and screened a portion of individuals with LCA. C.A., R.A., H.V.G. and E.V. contributed samples for the LCA study. F.B., I.L., A.M.S. and C.M.L. performed genetic screening and genotyping. M.A.L. performed biochemical assays. C.M.L. and J.G.G. wrote the manuscript with contributions from E.M.V., G.C., D.S.W., V.S.L., F.H., F.B. and A.K.

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Correspondence to Joseph G Gleeson.

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Louie, C., Caridi, G., Lopes, V. et al. AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis. Nat Genet 42, 175–180 (2010). https://doi.org/10.1038/ng.519

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