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


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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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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Authors and Affiliations



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).

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