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Review
. 2007 Dec;117(12):3603-9.
doi: 10.1172/JCI33297.

Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders

Joost P H Drenth  1 , Stephen G Waxman
Affiliations
Review

Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders

Joost P H Drenth et al. J Clin Invest. 2007 Dec.

Abstract

The voltage-gated sodium-channel type IX alpha subunit, known as Na(v)1.7 and encoded by the gene SCN9A, is located in peripheral neurons and plays an important role in action potential production in these cells. Recent genetic studies have identified Na(v)1.7 dysfunction in three different human pain disorders. Gain-of-function missense mutations in Na(v)1.7 have been shown to cause primary erythermalgia and paroxysmal extreme pain disorder, while nonsense mutations in Na(v)1.7 result in loss of Na(v)1.7 function and a condition known as channelopathy-associated insensitivity to pain, a rare disorder in which affected individuals are unable to feel physical pain. This review highlights these recent developments and discusses the critical role of Na(v)1.7 in pain sensation in humans.

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Figures

Figure 1
Figure 1. Mutations in the sodium-channel subunit Nav1.7 that are associated with the genetic pain disorders PE, PEPD, and CIP.
(A) Nav1.7 is encoded by the 113.5-kb gene SCN9A, comprising 26 coding exons. The identity and location of known patient mutations in Nav1.7 that have been linked to PE (*), PEPD (^), and CIP (#) are shown. Note that the mutations are spread over the entire gene sequence; however, mutations linked to PEPD tend to be located closer to the 3′ end of the gene. (B) A schematic of the Nav1.7 sodium-channel subunit showing the 4 domains (D1–D4), each with 6 transmembrane segments. Locations of known mutations associated with genetic pain disorders PE, PEPD, and CIP are shown. COOH indicates the C-terminus of the peptide chain. HN indicates the N-terminus of the peptide chain.
Figure 2
Figure 2. Neuronal Nav1.7 channels.
Nav1.7 (shown here in red after immunocytostaining with anti-Nav1.7 antibody; Alomone Reagents) within the tip of a growing neurite from rat DRG neuron in culture. Image kindly provided by Joel A. Black, Department of Neurology, Yale University, New Haven, Connecticut, USA.
Figure 3
Figure 3. Red feet and lower legs in a patient with primary erythermalgia.
Image courtesy of The Erythromelalgia Association.
Figure 4
Figure 4. Four clinical situations in which Nav1.7 channel activity is altered.
PE and PEPD are autosomal dominant (AD) conditions, while CIP is inherited via an autosomal recessive (AR) trait. The mutations of the Nav1.7 channel grossly dictate that there is a gain of function (increased channel activity) in PE and PEPD, while Nav1.7 channel function is lost (absent) in CIP. The resultant phenotype is reflected in the lower row. In humans, the Nav1.7 mutations result in pain in the feet and hands (in PE) or ocular, mandibular, and/or rectal pain (in PEPD). In CIP, there is a loss of Nav1.7 channel function, resulting in an inability to register pain.
See this image and copyright information in PMC

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