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SODIUM VOLTAGE-GATED CHANNEL, ALPHA SUBUNIT 11; SCN11A

SODIUM VOLTAGE-GATED CHANNEL, ALPHA SUBUNIT 11; SCN11A

Alternative titles; symbolsSODIUM CHANNEL, VOLTAGE-GATED, TYPE XI, ALPHA SUBUNITNAV1.9HGNC Approved Gene Symbol: SCN11ACytogenetic location: 3p22.2 Genomic c...

Alternative titles; symbols

  • SODIUM CHANNEL, VOLTAGE-GATED, TYPE XI, ALPHA SUBUNIT
  • NAV1.9

HGNC Approved Gene Symbol: SCN11A

Cytogenetic location: 3p22.2 Genomic coordinates (GRCh38): 3:38,845,763-39,051,943 (from NCBI)

▼ Description
The SCN11A gene encodes a voltage-gated sodium channel that is highly expressed in nociceptive neurons of dorsal root ganglia and trigeminal ganglia and is a major effector of peripheral inflammatory pain hypersensitivity (summary by Zhang et al., 2013).

Voltage-gated sodium channels are membrane protein complexes that play a fundamental role in the rising phase of the action potential in most excitable cells. Alpha subunits mediate voltage-dependent gating and conductance, while auxiliary beta subunits regulate the kinetic properties of the channel and facilitate membrane localization of the complex. Aberrant expression patterns or mutations of alpha subunits underlie a number of disorders. Each alpha subunit consists of 4 domains connected by 3 intracellular loops; each domain consists of 6 transmembrane segments and intra- and extracellular linkers.

▼ Cloning and Expression
Dib-Hajj et al. (1998) determined that rat NaN, encoded by the Scn11a gene, is preferentially expressed in small sensory neurons of dorsal root ganglia and trigeminal ganglia. Dib-Hajj et al. (1999) sequenced the 1,765-amino acid mouse NaN protein, which is predicted to produce a current that is resistant to tetrodotoxin.

By EST database searching followed by PCR and 5-prime and 3-prime RACE of human brain RNA, Jeong et al. (2000) cloned a full-length cDNA encoding SCN11A, which they called SCN12A. The deduced 1,791-amino acid protein has a calculated molecular mass of 205 kD and contains several domains conserved between alpha subunits, including 4 internal repeat domains (I to IV), each having 6 putative alpha-helical transmembrane segments and 2 pore-lining segments. Other conserved elements include positively charged residues in the voltage sensor, multiple putative sites for cAMP-dependent phosphorylation in loops 1 and 2, and the inactivation gates in loop 3. A serine residue (ser360) is predicted to confer tetrodotoxin resistance. Jeong et al. (2000) also cloned a truncated variant encoding a 1,444-amino acid protein that lacks domain IV and the C-terminal region. Overall, SCN11A shares 73% similarity with rat Scn11a. Northern blot analysis of multiple tissues revealed expression of a 7.0-kb transcript predominantly in brain, spinal cord, spleen, small intestine, and placenta. SCN11A was expressed in all central nervous system (CNS) areas examined. In situ hybridization of rat tissues revealed broad expression in the CNS, particularly in the gray matter of the hippocampus, in the cerebellum, and in the olfactory bulb. It was also expressed in germinal center cells of spleen and trophoblasts of placenta. RT-PCR of several human cell lines revealed predominant expression in neurons and lower expression in glia cell lines.

▼ Mapping
By radiation hybrid analysis, Dib-Hajj et al. (1999) mapped the human SCN11A gene to chromosome 3p24-p21, close to the genes for 2 other tetrodotoxin-resistant voltage-gated sodium channels, SCN5A (600163) and SCN10A (604427). The colocalization of the 3 sodium channel genes supports a common lineage of the tetrodotoxin-resistant sodium channels.

By FISH, Jeong et al. (2000) mapped the SCN11A gene to chromosome 3p23-p21.3.

Gross (2013) mapped the SCN11A gene to chromosome 3p22.2 based on an alignment of the SCN11A sequence (GenBank AJ417790) with the genomic sequence (GRCh37).

By interspecific backcross mapping, Dib-Hajj et al. (1999) assigned the mouse Scn11a gene to chromosome 9, close to the Scn5a and Scn10a genes.

▼ Gene Function
By patch-clamp recording of rat hippocampal slices and a human neuroblastoma cell line, and by cotransfections in HEK293 cells, Blum et al. (2002) determined that SCN11A, which they called Na(v)1.9, mediates brain-derived neurotrophic factor (BDNF; 113505)-evoked membrane depolarization through the receptor tyrosine kinase NTRK2 (600456).

▼ Molecular Genetics
Hereditary Sensory and Autonomic Neuropathy, Type VII

In 2 unrelated patients with hereditary sensory and autonomic neuropathy type VII (HSAN7; 615548) manifest mainly by congenital inability to experience pain, Leipold et al. (2013) identified the same de novo heterozygous missense mutation in the SCN11A gene (L811P; 604385.0001). The mutation in the first patient was found by whole-exome sequencing. The second mutation was found by sequencing of the SCN11A gene in 58 individuals with early-onset severe sensory loss. Transfection of the mutation into mice resulted in reduced pain sensitivity. Electrophysiologic studies in dorsal root ganglia from mutant mice and in isolated cells showed that the mutation resulted in a gain of function with a left-shift in the resting membrane potential and channel activation, and a decrease in the kinetics of channel deactivation. Leipold et al. (2013) hypothesized that this excess sodium influx and subsequent cell depolarization at rest may cause progressive conduction block in other ion channels that form the main constituents of the action potential in dorsal root ganglia neurons. Insufficient activation of calcium ion channels would result in impaired neurotransmitter release at presynaptic nerve terminals to transmit pain signals to the spinal cord.

In a patient with debilitating pruritus and altered pain perception consistent with HSAN7, Salvatierra et al. (2018) identified de novo heterozygosity for the L811P mutation in the SCN11A gene. Using fluorescence tagging of the sodium channel in a mouse model, the authors showed that the channel is present in a subset of nonmyelinated, nonpeptidergic small-diameter dorsal root ganglia. Compared with control mice, mice with global knockout of the Scn11a gene showed reduced scratching behavior on application of pruritogens. Mice heterozygous for the L799P variant exhibited amplified scratching behavior in rest conditions, providing evidence for involvement of SCN11A in pruritus.

Familial Episodic Pain Syndrome 3

In 2 unrelated Chinese families with autosomal dominant familial episodic pain syndrome-3 (FEPS3; 615552), Zhang et al. (2013) identified 2 different heterozygous missense mutations in the SCN11A gene (R225C, 604385.0002 and A808G, 604385.0003). The mutation in the first family was found by genomewide linkage analysis combined with whole-exome sequencing. The phenotype was characterized by onset in early childhood of episodic pain localized primarily to the distal lower extremities and occasionally in the upper body, especially in the joints of fingers and arms. Episodic pain appeared late in the day and occurred in cycles. The pain was exacerbated with fatigue, such as catching a cold or performing hard exercise, and was relieved by oral administration of antiinflammatory analgesic medicines. Electrophysiologic studies in mouse dorsal root ganglia neurons showed that both mutations had higher peak current densities compared to wildtype, indicating higher electrical activity. Mutant channels also showed increased spontaneous firing compared to wildtype. However, voltage dependence for activation and inactivation kinetics of mutant channels were similar to wildtype. Neurons expressing the A808G mutation fired more action potentials than those expressing the R225C mutation, which was consistent with the increased number of episodic pain episodes in the family carrying the A808G mutation. Zhang et al. (2013) noted that the SCN11A channel is not directly responsible for action potential generation, and suggested that higher electrical activities of the mutant channels may induce the opening of other sodium channels, such as SCN10A (604427), and thus cause dorsal root ganglion neurons to be hyperexcitable, which would contribute to the episodic pain syndrome.

In 12 unrelated patients with FEPS3 manifest as adult-onset painful small fiber peripheral neuropathy (see 615552), Huang et al. (2014) identified 7 different heterozygous missense mutations in the SCN11A gene (see, e.g., L1158P, 604385.0004 and I381T, 604385.0005). The 12 patients were identified from a group of 345 unrelated patients with a clinical diagnosis of small fiber neuropathy. Four of the mutations affected conserved residues in membrane-spanning segments of the channel. Electrophysiologic studies showed that the L1158P and I381T mutations conferred a gain of function by depolarizing the resting membrane potential of dorsal root ganglion neurons, enhancing spontaneous firing, and increasing evoked firing of these neurons. In addition to painful peripheral neuropathy, all the patients had a number of complaints associated with autonomic dysfunction.

▼ Animal Model
Priest et al. (2005) found that Scn11a-null mice were not significantly different from age- and gender-matched wildtype littermates. Voltage-clamp recordings of dissociated dorsal root ganglion (DRG) neurons indicated that Na(v)1.9 does not contribute to resting membrane potential, action potential characteristics, or pain perception. However, Na(v)1.9 contributed to the persistent tetrodotoxin-resistant current in small-diameter DRG neurons and to the persistent thermal hypersensitivity and spontaneous pain behavior following exposure to inflammatory mediators. Priest et al. (2005) concluded that inflammatory mediators modify the function of Na(v)1.9 to maintain inflammation-induced hyperalgesia.

▼ ALLELIC VARIANTS ( 5 Selected Examples):

.0001 NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE VII
SCN11A, LEU811PRO
In a German girl with hereditary sensory and autonomic neuropathy type VII (HSAN7; 615548) manifest mainly as congenital inability to experience pain, Leipold et al. (2013) identified a de novo heterozygous c.2432T-C transition in exon 15 of the SCN11A gene, resulting in a leu811-to-pro (L811P) substitution at a highly conserved residue at the distal end of the sixth transmembrane segment in domain 2, which forms part of the channel gate. The mutation was found by whole-exome sequencing and was not present in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases. Sequencing of the SCN11A gene in 58 probands with early-onset severe sensory loss identified the same de novo mutation in 1 Swedish patient. After transfection with the orthologous mouse mutation (L799P), 11% of heterozygous mice showed severe tissue injuries that appeared to be self-inflicted. Mutant mice also had a higher threshold for noxious heat stimuli compared to controls, consistent with reduced pain sensitivity. Miniature excitatory postsynaptic currents in spinal cord dorsal root ganglia were less frequent compared to controls. Studies of dorsal root ganglion neurons from heterozygous mutant mice showed a leftward shift in the resting membrane potential compared to wildtype, indicating that a number of channels are active under resting conditions, as well as a leftward shift in the voltage-dependence of activation. These changes were associated with a shorter duration of action potentials and less pronounced hyperpolarization afterwards compared to controls. Patch-clamp recordings showed that the heterozygous mutant cells had diminished peak current densities at depolarized voltages, as well as augmentation of channel activity at rest compared to wildtype, which slowed down the kinetics of channel deactivation. Overall, the findings were consistent with a gain-of-function phenotype mediated by a left-shift in channel activation. Leipold et al. (2013) hypothesized that this excess sodium influx and subsequent cell depolarization at rest may cause progressive conduction block in other ion channels that form the main constituents of the action potential in dorsal root ganglia neurons. Insufficient activation of calcium ion channels would result in impaired neurotransmitter release at presynaptic nerve terminals to transmit pain signals to the spinal cord.

In a Scottish patient with HSAN7, Woods et al. (2015) identified de novo heterozygosity for the L811P mutation in the SCN11A gene.

Salvatierra et al. (2018) identified de novo heterozygosity for the L799P mutation in the SCN11A gene in a patient with debilitating pruritus and altered pain perception consistent with HSAN7. In a mouse model, Scn11a null mice exhibited a strong reduction in acute scratching behavior in response to pruritogens, whereas mice heterozygous for the L799P variant exhibited amplified scratching behavior in rest conditions, similar to the phenotype seen in humans, providing evidence for participation of SCN11A gene in pruritus.

.0002 EPISODIC PAIN SYNDROME, FAMILIAL, 3
SCN11A, ARG225CYS
In affected members of a large multigenerational Chinese family with familial episodic pain syndrome-3 (FEPS3; 615552), Zhang et al. (2013) identified a c.673C-T transition in the SCN11A gene, resulting in an arg225-to-cys (R225C) substitution at a highly conserved residue in transmembrane segment S4. The mutation was found by genomewide linkage analysis combined with whole-exome sequencing. The mutation fully segregated with the disorder in the family and was not present in the dbSNP (build 132), 1000 Genomes Project, or Exome Sequencing Project databases, or in 1,021 unrelated Han individuals. Electrophysiologic studies in mouse dorsal root ganglia neurons showed that the mutation had a 23% higher peak current density compared to wildtype, indicating higher electrical activity. Mutant channels also showed increased spontaneous firing compared to wildtype. However, voltage-dependence for activation and inactivation kinetics for mutant channels were similar to wildtype.

.0003 EPISODIC PAIN SYNDROME, FAMILIAL, 3
SCN11A, ALA808GLY
In affected members of a Chinese family with familial episodic pain syndrome-3 (FEPS3; 615552), Zhang et al. (2013) identified a heterozygous c.2423C-G transversion in the SCN11A gene, resulting in an ala808-to-gly (A808G) substitution at a highly conserved residue in the transmembrane segment S6. The mutation fully segregated with the disorder in the family and was not present in the dbSNP (build 132), 1000 Genomes Project, or Exome Sequencing Project databases, or in 1,021 unrelated Han individuals. Electrophysiologic studies in mouse dorsal root ganglia neurons showed that the mutation had a 30% higher peak current density compared to wildtype, indicating higher electrical activity. Mutant channels also showed increased spontaneous firing compared to wildtype. However, voltage-dependence for activation and inactivation kinetics of mutant channels were similar to wildtype.

.0004 EPISODIC PAIN SYNDROME, FAMILIAL, 3
SCN11A, LEU1158PRO
In 2 unrelated patients with familial episodic pain syndrome-3 (FEPS3; 615552), manifest as adult-onset small fiber neuropathy, Huang et al. (2014) identified a heterozygous c.3473T-C transition in exon 20 of the SCN11A gene, resulting in a leu1158-to-pro (L1158P) substitution at a highly conserved residue in the domain III/S4 region, which is the voltage sensor for this domain. DNA from family members was not available for segregation studies. Patch-clamp recordings and electrophysiologic studies in rat dorsal root ganglion neurons transfected with the L1158P mutation had a depolarized resting membrane potential, slowed deactivation of action potentials, reduced current threshold, and increased firing frequency in response to stimulus compared to wildtype, consistent with hyperexcitability and a gain of function.

.0005 EPISODIC PAIN SYNDROME, FAMILIAL, 3
SCN11A, ILE381THR
In 2 unrelated patients with familial episodic pain syndrome-3 (FEPS3; 615552), manifest as adult-onset small fiber neuropathy, Huang et al. (2014) identified a heterozygous c.1142T-C transition in exon 9 of the SCN11A gene, resulting in an ile381-to-thr (I381T) substitution at a highly conserved residue in the domain I transmembrane 6 (DI/S6) region, a pore-lining segment of the channel. DNA from family members was not available for segregation studies. Patch-clamp recordings and electrophysiologic studies in rat dorsal root ganglion neurons transfected with the I381T mutation had a depolarized resting membrane potential, slowed deactivation of action potentials, reduced current threshold, and increased firing frequency in response to stimulus as well as spontaneously compared to wildtype, consistent with hyperexcitability and a gain of function.

Tags: 3p22.2