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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hasin-Brumshtein, Y., Lancet, D. & Olender, T. Human olfaction: from genomic variation to phenotypic diversity. Trends Genet. 25, 178–184 (2009)
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)
Keller, A. & Vosshall, L. B. Better smelling through genetics: mammalian odor perception. Curr. Opin. Neurobiol. 18, 364–369 (2008)
Goldin, A. L. Resurgence of sodium channel research. Annu. Rev. Physiol. 63, 871–894 (2001)
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)
Cox, J. J. et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 444, 894–898 (2006)
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)
Ahmad, S. et al. A stop codon mutation in SCN9A causes lack of pain sensation. Hum. Mol. Genet. 16, 2114–2121 (2007)
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)
Nilsen, K. B. et al. Corrigendum to “Two novel SCN9A mutations causing insensitivity to pain.” Pain . 145, 264 (2009)
Munger, S. D., Leinders-Zufall, T. & Zufall, F. Subsystem organization of the mammalian sense of smell. Annu. Rev. Physiol. 71, 115–140 (2009)
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)
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)
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)
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)
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)
Belluscio, L., Gold, G. H., Nemes, A. & Axel, R. Mice deficient in Golf are anosmic. Neuron 20, 69–81 (1998)
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)
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)
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)
Munger, S. D. et al. Central role of the CNGA4 channel subunit in Ca2+-calmodulin-dependent odor adaptation. Science 294, 2172–2175 (2001)
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)
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)
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)
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)
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)
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)
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)
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)
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)
Kobayakawa, K. et al. Innate versus learned odour processing in the mouse olfactory bulb. Nature 450, 503–508 (2007)
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)
Sakano, H. Neural map formation in the mouse olfactory system. Neuron 67, 530–542 (2010)
Pyrski, M. et al. Sodium/calcium exchanger expression in the mouse and rat olfactory systems. J. Comp. Neurol. 501, 944–958 (2007)
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)
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)
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)
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.
The authors declare no competing financial interests.
About this article
Cite this article
Weiss, J., Pyrski, M., Jacobi, E. et al. Loss-of-function mutations in sodium channel Nav1.7 cause anosmia. Nature 472, 186–190 (2011) doi:10.1038/nature09975
Bioorganic & Medicinal Chemistry Letters (2019)
Challenges and Opportunities for Therapeutics Targeting the Voltage-Gated Sodium Channel Isoform NaV1.7
Journal of Medicinal Chemistry (2019)
Understanding Genotypes and Phenotypes of the Mutations in Voltage- Gated Sodium Channel α Subunits in Epilepsy
CNS & Neurological Disorders - Drug Targets (2019)
Antiallodynic effects of the selective NaV1.7 inhibitor Pn3a in a mouse model of acute postsurgical pain
Neuroscience Letters (2019)