You are here

Gain-of-function mutations in sodium channel NaV1.9 in painful neuropathy.

Editors' Pick
Gain-of-function mutations in sodium channel NaV1.9 in painful neuropathy.
Huang J, Han C, Estacion M, Vasylyev D, Hoeijmakers JGJ, Gerrits MM, Tyrrell L, Lauria G, Faber CG, Dib-Hajj SD, Merkies ISJ, Waxman SG
Brain. 2014 Jun; 137(Pt 6):1627-42. Epub 2014 Apr 27.
PMID: 24776970.

Comments on Related Content

Comment on News:
May 16 2014

Geoffrey Woods, University of Cambridge

SCN11A (and its protein product Nav1.9) now has its due recognition as an important pain channel in humans, and presumably all other vertebrates. 

Work by Ingo Kurth's team in Germany (Leipold et al., 2013) on two individuals with a new congenital insensitivity to pain (CIP) started the ball rolling. These individuals felt no pain but had a sense of smell (distinguishing this from SCN9A/Nav1.7 CIP). Kurth's team showed that the heterozygous mutation found in both cases, L811P, caused elevation to resting membrane potential in electrophysiological studies but hypo-activity in dorsal root ganglia pain neurons. 

Then came the work of Liu's team from China (Zhang et al., 2013), who reported two dominant Chinese families with a strange episodic pain phenotype which affected the extremities intermittently, became worse with extremes of temperature and activity, and tended to improve with age (the opposite pattern for SCN9A activating mutations that caused episodic pain). They found a different mutation in each family in SCN11A/Nav1.9, R225C, and A808G, and showed that these were activating. 

And now we have a report from Stephen Waxman's team of SCN11A/Nav1.9 heterozygous mutations causing small-fiber neuropathy. Some background: Waxman's team has studied a carefully curated cohort of Dutch individuals with late-onset peripheral pain diagnosed as due to small-fiber neuropathy (pain neurons transmit their action potentials in the smallest nerve fibers). They found mutations (most proved to be pathogenic) in SCN9A in about 9 percent and SCN10A in about 4 percent, and now in SCN11A in about 3 percent. In their recent paper, they go on to characterize two mutations (each found in two different cases) and show them to alter the resting membrane potential from a negative potential to a not so negative potential, and that this rendered cells and pain neurons hyperexcitable. 

So this new study further highlights that SCN11A/Nav1.9 is an important pain target for further study—even though it is a relatively rare cause of Mendelian pain disorders. But it also throws up new problems. Firstly, we now have activating mutations in SCN11A/Nav1.9 that cause three very distinct pain syndromes—with a spread of phenotype that is difficult to explain at present. Secondly, the mutations described by the three teams all seem to affect the resting cell membrane potential and make it less negatively charged—but with differences in activity in DRG pain neurons. 

Maybe we have been na├»ve in expecting SCN11A to have a simple phenotype-to-genotype relationship. As more work is performed on SCN9A/Nav1.7 mutations, we are finding a diversity of effects on cells, and we still have the unexplained difference in phenotype between paroxysmal extreme pain and congenital erythromelalgia (one presents from birth, the other decades later; one causes rectal pain, one doesn't, etc.). SCN11A/Nav1.9 is strongly expressed in the neuronal plexus that controls gut motility, while SCN9A/Nav1.7 is strongly expressed in the autonomic nervous system. Maybe the emerging sophisticated genotype/phenotype/electrophysiological studies are showing us that these voltage-gated sodium channels have different modes of activity in different parts of the nervous system? 

It is clear that what is needed are high-quality data. Mutations in SCN9A, SCN10A, and SCN11A are now easy to find with the wide availability of cheap, next-generation DNA sequencing. What will be essential is that mutations found are properly examined by clinical means For example, the Waxman paper did not perform family studies of the mutations, so we don't know if the mutations cause a consistent phenotype or not. Similarly, the Liu paper does not give sufficient clinical data. None of the studies have comprehensively ruled out changes in other ion channels that may be affecting results, and none have looked in neuron models of all of the types of neurons that could contribute to the holistic human phenotypes reported. So more research, more publications, and more data, please!