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Loss-of-function mutations in sodium channel Nav1.7 cause anosmia

Abstract

Loss of function of the gene SCN9A, encoding the voltage-gated sodium channel Nav1.7, causes a congenital inability to experience pain in humans. Here we show that Nav1.7 is not only necessary for pain sensation but is also an essential requirement for odour perception in both mice and humans. We examined human patients with loss-of-function mutations in SCN9A and show that they are unable to sense odours. To establish the essential role of Nav1.7 in odour perception, we generated conditional null mice in which Nav1.7 was removed from all olfactory sensory neurons. In the absence of Nav1.7, these neurons still produce odour-evoked action potentials but fail to initiate synaptic signalling from their axon terminals at the first synapse in the olfactory system. The mutant mice no longer display vital, odour-guided behaviours such as innate odour recognition and avoidance, short-term odour learning, and maternal pup retrieval. Our study creates a mouse model of congenital general anosmia and provides new strategies to explore the genetic basis of the human sense of smell.

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Figure 1: Na v 1.7 in human olfaction.
Figure 2: Na v 1.7 expression in the mouse main olfactory system.
Figure 3: Na v 1.7 is essential for synaptic transfer in the olfactory glomerulus.
Figure 4: cNa v 1.7 −/− mice are anosmic.

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References

  1. Hasin-Brumshtein, Y., Lancet, D. & Olender, T. Human olfaction: from genomic variation to phenotypic diversity. Trends Genet. 25, 178–184 (2009)

    Article  CAS  Google Scholar 

  2. Feldmesser, E. et al. Mutations in olfactory signal transduction genes are not a major cause of human congenital general anosmia. Chem. Senses 32, 21–30 (2007)

    Article  CAS  Google Scholar 

  3. Keller, A. & Vosshall, L. B. Better smelling through genetics: mammalian odor perception. Curr. Opin. Neurobiol. 18, 364–369 (2008)

    Article  CAS  Google Scholar 

  4. Goldin, A. L. Resurgence of sodium channel research. Annu. Rev. Physiol. 63, 871–894 (2001)

    Article  CAS  Google Scholar 

  5. Catterall, W. A., Goldin, A. L. & Waxman, S. G. International Union of Pharmacology. XLVII. Nomenclature and structure–function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57, 397–409 (2005)

    Article  CAS  Google Scholar 

  6. Cox, J. J. et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 444, 894–898 (2006)

    Article  ADS  CAS  Google Scholar 

  7. Goldberg, Y. P. et al. Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations. Clin. Genet. 71, 311–319 (2007)

    Article  CAS  Google Scholar 

  8. Ahmad, S. et al. A stop codon mutation in SCN9A causes lack of pain sensation. Hum. Mol. Genet. 16, 2114–2121 (2007)

    Article  CAS  Google Scholar 

  9. Dib-Hajj, S. D., Cummins, T. R., Black, J. A. & Waxman, S. G. From genes to pain: Nav1.7 and human pain disorders. Trends Neurosci. 30, 555–563 (2007)

    Article  CAS  Google Scholar 

  10. Nilsen, K. B. et al. Corrigendum to “Two novel SCN9A mutations causing insensitivity to pain.” Pain . 145, 264 (2009)

    Article  CAS  Google Scholar 

  11. Munger, S. D., Leinders-Zufall, T. & Zufall, F. Subsystem organization of the mammalian sense of smell. Annu. Rev. Physiol. 71, 115–140 (2009)

    Article  CAS  Google Scholar 

  12. Nassar, M. A. et al. Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc. Natl Acad. Sci. USA 101, 12706–12711 (2004)

    Article  ADS  CAS  Google Scholar 

  13. Li, J., Ishii, T., Feinstein, P. & Mombaerts, P. Odorant receptor gene choice is reset by nuclear transfer from mouse olfactory sensory neurons. Nature 428, 393–399 (2004)

    Article  ADS  CAS  Google Scholar 

  14. Klugbauer, N., Lacinova, L., Flockerzi, V. & Hofmann, F. Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells. EMBO J. 14, 1084–1090 (1995)

    Article  CAS  Google Scholar 

  15. Morinville, A. et al. Distribution of the voltage-gated sodium channel Nav1.7 in the rat: expression in the autonomic and endocrine systems. J. Comp. Neurol. 504, 680–689 (2007)

    Article  CAS  Google Scholar 

  16. Baker, H., Grillo, M. & Margolis, F. L. Biochemical and immunocytochemical characterization of olfactory marker protein in the rodent central nervous system. J. Comp. Neurol. 285, 246–261 (1989)

    Article  CAS  Google Scholar 

  17. Belluscio, L., Gold, G. H., Nemes, A. & Axel, R. Mice deficient in Golf are anosmic. Neuron 20, 69–81 (1998)

    Article  CAS  Google Scholar 

  18. Zhao, H. & Reed, R. R. X inactivation of the OCNC1 channel gene reveals a role for activity-dependent competition in the olfactory system. Cell 104, 651–660 (2001)

    Article  CAS  Google Scholar 

  19. Spehr, M. et al. Essential role of the main olfactory system in social recognition of major histocompatibility complex peptide ligands. J. Neurosci. 26, 1961–1970 (2006)

    Article  CAS  Google Scholar 

  20. Leinders-Zufall, T. et al. Contribution of the receptor guanylyl cyclase GC-D to chemosensory function in the olfactory epithelium. Proc. Natl Acad. Sci. USA 104, 14507–14512 (2007)

    Article  ADS  CAS  Google Scholar 

  21. Munger, S. D. et al. Central role of the CNGA4 channel subunit in Ca2+-calmodulin-dependent odor adaptation. Science 294, 2172–2175 (2001)

    Article  ADS  CAS  Google Scholar 

  22. Shepherd, G. M., Chen, W. R. & Greer, C. A. in The Synaptic Organization of the Brain (ed. Shepherd, G. M. ) 165–216 (Oxford Univ. Press, 2004)

    Book  Google Scholar 

  23. Wachowiak, M. & Shipley, M. T. Coding and synaptic processing of sensory information in the glomerular layer of the olfactory bulb. Semin. Cell Dev. Biol. 17, 411–423 (2006)

    Article  Google Scholar 

  24. Nickell, W. T., Shipley, M. T. & Behbehani, M. M. Orthodromic synaptic activation of rat olfactory bulb mitral cells in isolated slices. Brain Res. Bull. 39, 57–62 (1996)

    Article  CAS  Google Scholar 

  25. Gabellec, M. M., Panzanelli, P., Sassoe-Pognetto, M. & Lledo, P. M. Synapse-specific localization of vesicular glutamate transporters in the rat olfactory bulb. Eur. J. Neurosci. 25, 1373–1383 (2007)

    Article  Google Scholar 

  26. Richard, M. B., Taylor, S. R. & Greer, C. A. Age-induced disruption of selective olfactory bulb synaptic circuits. Proc. Natl Acad. Sci. USA 107, 15613–15618 (2010)

    Article  ADS  CAS  Google Scholar 

  27. Yu, C. R. et al. Spontaneous neural activity is required for the establishment and maintenance of the olfactory sensory map. Neuron 42, 553–566 (2004)

    Article  CAS  Google Scholar 

  28. Puche, A. C. & Shipley, M. T. Odor-induced, activity-dependent transneuronal gene induction in vitro: mediation by NMDA receptors. J. Neurosci. 19, 1359–1370 (1999)

    Article  CAS  Google Scholar 

  29. Cho, J. Y., Min, N., Franzen, L. & Baker, H. Rapid down-regulation of tyrosine hydroxylase expression in the olfactory bulb of naris-occluded adult rats. J. Comp. Neurol. 369, 264–276 (1996)

    Article  CAS  Google Scholar 

  30. Baker, H. et al. Targeted deletion of a cyclic nucleotide-gated channel subunit (OCNC1): biochemical and morphological consequences in adult mice. J. Neurosci. 19, 9313–9321 (1999)

    Article  CAS  Google Scholar 

  31. Kobayakawa, K. et al. Innate versus learned odour processing in the mouse olfactory bulb. Nature 450, 503–508 (2007)

    Article  ADS  CAS  Google Scholar 

  32. Wesson, D. W., Levy, E., Nixon, R. A. & Wilson, D. A. Olfactory dysfunction correlates with amyloid-β burden in an Alzheimer's disease mouse model. J. Neurosci. 30, 505–514 (2010)

    Article  CAS  Google Scholar 

  33. Sakano, H. Neural map formation in the mouse olfactory system. Neuron 67, 530–542 (2010)

    Article  CAS  Google Scholar 

  34. Pyrski, M. et al. Sodium/calcium exchanger expression in the mouse and rat olfactory systems. J. Comp. Neurol. 501, 944–958 (2007)

    Article  CAS  Google Scholar 

  35. Au, W. W., Treloar, H. B. & Greer, C. A. Sublaminar organization of the mouse olfactory bulb nerve layer. J. Comp. Neurol. 446, 68–80 (2002)

    Article  Google Scholar 

  36. Ukhanov, K., Leinders-Zufall, T. & Zufall, F. Patch-clamp analysis of gene-targeted vomeronasal neurons expressing a defined V1r or V2r receptor: ionic mechanisms underlying persistent firing. J. Neurophysiol. 98, 2357–2369 (2007)

    Article  CAS  Google Scholar 

  37. Papes, F., Logan, D. W. & Stowers, L. The vomeronasal organ mediates interspecies defensive behaviors through detection of protein pheromone homologs. Cell 141, 692–703 (2010)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the individuals who participated in this study, P. Mombaerts for supplying OMP–Cre and OMP–GFP mice, F. Margolis for anti-OMP antibodies, J. Epelbaum for supporting the IGF-1 measurements, P. Hammes for assistance with the immunohistochemistry and C. Kaliszewski for assistance with the electron microscopy. This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) to F.Z. (SFB 530 and SFB 894) and T.L.-Z. (SFB 894). E.J. was supported by the DFG-funded International Graduate School GK 1326. T.L.-Z. is a Lichtenberg Professor of the Volkswagen Foundation. J.N.W. was supported by the Biotechnology and Biological Sciences Research Council, Medical Research Council, Wellcome Trust and grant number R31-2008-000-10103-0 from the World Class University project of the Korean Ministry of Education, Science and Technology and the National Research Foundation of Korea.

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Contributions

J.N.W. and F.Z. conceived the study. J.W., M.P., E.J., B.B. and P.Z. performed experiments. B.S. performed human biopsies. C.G.W., S.J.G. and J.N.W. performed human smell tests. J.W., M.P., E.J., B.B., V.W., P.Z., S.J.G., C.A.G., T.L.-Z., C.G.W., J.N.W. and F.Z. analysed results. M.P., T.L.-Z., J.N.W. and F.Z. contributed key reagents. F.Z. wrote the manuscript. All authors edited the manuscript.

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Correspondence to Frank Zufall.

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The authors declare no competing financial interests.

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Weiss, J., Pyrski, M., Jacobi, E. et al. Loss-of-function mutations in sodium channel Nav1.7 cause anosmia. Nature 472, 186–190 (2011). https://doi.org/10.1038/nature09975

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