SCN9A

Gene Name:

sodium channel, voltage-gated, type IX, alpha subunit

Synonyms:

Nav1.7; FEB3B; NENA; ETHA2; PN1; GEFSP7; Sodium Channel, Voltage-Gated, Type IX, Alpha Polypeptide; Neuroendocrine Sodium Channel, Peripheral Sodium Channel 1, SFNP

Chromosome:

Chromosomal Location:

167,051,704: 167,232,497

Entrez Gene ID:

6335

OMIM ID:

603415

Protein Name:

sodium channel protein type 9 subunit alpha; Nav1.7 sodium channel type 9 subunit alpha

UNIPROT ID:

Q15858

Function:

voltage-gated sodium channel Nav1.7 subunit

Phenotype/Disease:

erythermalgia, PEPD, CIP, pain sensitivity

Pain Data in Humans:

SCN9A-v1

Variant Type:

autosomal dominant gain-of-function missense mutations

Variant ID:

more than 20 different mutations to date

Phenotype/Disease:

primary erythermalgia

OMIM Entry:

133020

Reference(s):

Yang et al., 2004

Cummins et al., 2004

Dib-Hajj et al., 2005

Han et al., 2006

Drenth et al., 2005

Michiels et al., 2005

Harty et al., 2006

Lee et al., 2007

Takahashi et al., 2007

Han et al., 2009

Choi et al., 2009

Fischer et al., 2009

Ahn et al., 2010

Skeik et al., 2012

Klein et al., 2013

Cregg et al., 2013

Estacion et al., 2013

Wu et al., 2013

Eberhardt et al., 2014

Meijer et al., 2014

Shorer et al., 2014

Notes:

Primary erythermalgia is characterized by attacks of burning pain and redness in distal extremities, often triggered by mild warmth and exercise. Mutations in Nav1.7 that cause erythermalgia appear to do so by enhancing channel activation and increasing dorsal root ganglion neuron excitability.

SCN9A-v2

Variant Type:

autosomal dominant gain-of-function missense mutations

Variant ID:

various missense mutations

Phenotype/Disease:

paroxysmal extreme pain disorder

OMIM Entry:

167400

Reference(s):

Fertleman et al., 2006

Choi et al., 2011

Notes:

Nav1.7 mutations that cause paroxysmal extreme pain disorder appear to impair fast channel inactivation, leading to persistent sodium current.

SCN9A-v3

Variant Type:

autosomal dominant gain-of-function missense mutation

Variant ID:

A1632E

Phenotype/Disease:

Symptoms of both erythermalgia and paroxysmal extreme pain disorder

Reference(s):

Estacion et al., 2008

scn9a-v4

Variant Type:

autosomal dominant gain-of-function missense mutations

Variant ID:

I720K, D623N, M932L+V991L, I228M

Phenotype/Disease:

small fiber neuropathy

OMIM Entry:

133020

Reference(s):

Editors' Pick

Faber et al., 2012

Han et al., 2012

SCN9A-v5

Variant Type:

autosomal dominant missense gain-of-function mutation

Variant ID:

G856D

Phenotype/Disease:

painful neuropathy with acromesomelia

Reference(s):

Hoeijmakers et al., 2012

SCN9A-v6

Variant Type:

autosomal dominant missense gain-of-function mutation

Variant ID:

I228M

Phenotype/Disease:

diverse pain phenotypes

Reference(s):

Estacion et al., 2011

Notes:

The mutation produced different pain syndromes in three carriers: severe facial pain, distal (feet and hands) pain, and scalp discomfort.

SCN9A-v7

Variant Type:

autosomal recessive loss-of-function mutations

Variant ID:

various truncating or deletion mutations

Phenotype/Disease:

congenital insensitivity to pain, channelopathy-associated

OMIM Entry:

243000

Reference(s):

Cox et al., 2006

Ahmad et al., 2007

Goldberg et al., 2007

Nilsen et al., 2009

Kurban et al., 2010

Cox et al., 2010

Weiss et al., 2011

Klein et al., 2013

Shorer et al., 2014

SCN9A-v8

Variant Type:

missense and splice site mutations

Variant ID:

C1719R/c.3467 + 3 delA, M899I, M932L

Phenotype/Disease:

partial insensitivity to pain

Reference(s):

Staud et al., 2011

Yuan et al., 2011

SCN9A-v9

Variant Type:

autosomal recessive mutation

Variant ID:

c.3993delGinsTT

Phenotype/Disease:

hereditary sensory and autonomic neuropathy

Reference(s):

Yuan et al., 2013

SCN9A-v10

Variant Type:

common polymorphism

SNP ID:

rs6746030G>A

SNP Type:

missense (R1150W)

Minor Allele:

Phenotype of Minor Allele:

increased pain sensitivity

Notes:

Studies have shown association of minor allele with increased pain sensitivity, increase in pain scores in patients with osteoarthritis, sciatica and phantom pain, or in a combined cohort with pain from various causes (Reimann et al., 2010). Minor allele was increased in small cohort with interstitial cystitis/bladder pain sydrome (Reeder et al., 2013); associated with risk of widespread pain (Valdes et al., 2011), and nominally associated with pain in Parkinson disease patients (Greenbaum et al., 2012). Negative studies: Valdes et al., 2011 report no association with OA pain in large cohort; Holliday et al., 2012 report no significant association with chronic widespread pain in mulitple cohorts.

SCN9A-v11

SNP ID:

rs41268673C>A

SNP Type:

missense (P610T)

Minor Allele:

Phenotype of Minor Allele:

modifies L858F erythermalgia phenotype

Reference(s):

Samuels et al., 2008

scn9A-v12

Variant Type:

common polymorphism

SNP ID:

unknown (3312G>T)

SNP Type:

missense (V1104L)

Minor Allele:

Phenotype of Minor Allele:

lower post operative pain sensitivity as measured by lower opioid consumption and lower incidence of inadequate analgesia

Reference(s):

Yuan et al., 2011

Duan et al., 2013

SCN9A-v13

Variant Type:

haplotype

SNP ID:

rs41268673C>A, rs6746030G>A

SNP Type:

missense (P610T, R1150W)

Minor Allele:

A, A

Phenotype of Minor Allele:

Higher number of carried minor alleles associated with increased pain sensitivity to blunt pressure stimuli (and increased olfactory acuity)

Reference(s):

Editors' Pick

Heimann et al., 2013

scn9A-v14

Variant Type:

common polymorphism

SNP ID:

rs6754031

SNP Type:

intron variant

Minor Allele:

Phenotype of Minor Allele:

frequency increased in patients with severe fibromyalgia

Reference(s):

Vargas-Alarcon et al., 2012

Notes:

Other tested SNPs showed no association in this small study of 73 Mexican women with fibromyalgia and 48 healthy controls: rs4371369; rs4387806; rs4453709; rs4597545; rs6746030; rs6754031; rs7607967; rs12620053; rs12994338; and rs13017637.

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SCN9A

SCN9A-v1

SCN9A-v2

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SCN9A-v8

SCN9A-v9

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