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Sulayman D Dibhajj - One of the best experts on this subject based on the ideXlab platform.

  • a 49 residue sequence motif in the c terminus of Nav1.9 regulates trafficking of the Channel to the plasma membrane
    Journal of Biological Chemistry, 2020
    Co-Authors: Daria V Sizova, Carolina Gomisperez, Stephen G Waxman, Mark Estacion, Elizabeth J. Akin, Jianying Huang, Sulayman D Dibhajj
    Abstract:

    : Genetic and functional studies have confirmed an important role for the voltage-gated Sodium Channel Nav1.9 in human pain disorders. However, low functional expression of Nav1.9 in heterologous systems, for example in human embryonic kidney 293 (HEK293) cells, has hampered studies of its biophysical and pharmacological properties, and the development of high-throughput assays for drug development targeting this Channel. The mechanistic basis for the low level of Nav1.9 currents in heterologous expression systems is not understood. Here, we implemented a multidisciplinary approach to investigate the mechanisms that govern functional Nav1.9 expression. Recombinant expression of a series of Nav1.9-Nav1.7 C-terminal chimeras in HEK293 cells identified a 49-amino-acid-long motif in the C-terminus of the two Channels that regulates expression levels of these chimeras. We confirmed the critical role of this motif in the context of a full-length Channel chimera, Nav1.9-Ct49aaNav1.7, which displayed significantly increased current density in HEK293 cells while largely retaining the characteristic Nav1.9-gating properties. High-resolution live microscopy indicated that the newly identified C-terminal motif dramatically increases the number of Channels on the plasma membrane of HEK293 cells. Molecular modeling results suggested that this motif is exposed on the cytoplasmic face of the folded C-terminus where it might interact with other Channel partners. These findings reveal that a 49-residue-long motif in Nav1.9 regulates Channel trafficking to the plasma membrane.

  • Sodium Channel genes in pain related disorders phenotype genotype associations and recommendations for clinical use
    Lancet Neurology, 2014
    Co-Authors: Sulayman D Dibhajj, Stephen G Waxman, Ingemar S J Merkies, Monique M Gerrits, Giuseppe Lauria, James J Cox, J Wood, Geoffrey C Woods
    Abstract:

    Human studies have firmly implicated voltage-gated Sodium Channels in human pain disorders, and targeted and massively parallel genomic sequencing is beginning to be used in clinical practice to determine which Sodium Channel variants are involved. Missense substitutions of SCN9A, the gene encoding Sodium Channel NaV1.7, SCN10A, the gene encoding Sodium Channel NaV1.8, and SCN11A, the gene encoding Sodium Channel Nav1.9, produce gain-of-function changes that contribute to pain in many human painful disorders. Genomic sequencing might help to establish a diagnosis, and in the future might support individualisation of therapeutic approaches. However, in many cases, and especially in Sodium Channelopathies, the results from genomic sequencing can only be appropriately interpreted in the context of an extensive functional assessment, or family segregation analysis of phenotype and genotype.

  • gain of function mutations in Sodium Channel na v 1 9 in painful neuropathy
    Brain, 2014
    Co-Authors: Jianying Huang, Mark Estacion, Monique M Gerrits, Giuseppe Lauria, Chongyang Han, Dymtro Vasylyev, Janneke G J Hoeijmakers, Lynda Tyrrell, Catharina G Faber, Sulayman D Dibhajj
    Abstract:

    Sodium Channel Nav1.9 is expressed in peripheral nociceptive neurons, as well as visceral afferents, and has been shown to act as a threshold Channel. Painful peripheral neuropathy represents a significant public health challenge and may involve gain-of-function variants in Sodium Channels that are preferentially expressed in peripheral sensory neurons. Although gain-of-function variants of peripheral Sodium Channels Nav1.7 and Nav1.8 have recently been found in painful small fibre neuropathy, the aetiology of peripheral neuropathy in many cases remains unknown. We evaluated 459 patients who were referred for possible painful peripheral neuropathy, and confirmed the diagnosis of small fibre neuropathy in a cohort of 393 patients (369 patients with pure small fibre neuropathy, and small fibre neuropathy together with large fibre involvement in an additional 24 patients). From this cohort of 393 patients with peripheral neuropathy, we sequenced SCN11A in 345 patients without mutations in SCN9A and SCN10A , and found eight variants in 12 patients. Functional profiling by electrophysiological recordings showed that these Nav1.9 mutations confer gain-of-function attributes to the Channel, depolarize resting membrane potential of dorsal root ganglion neurons, enhance spontaneous firing, and increase evoked firing of these neurons. Our data show, for the first time, missense mutations of Nav1.9 in individuals with painful peripheral neuropathy. These genetic and functional observations identify missense mutations of Nav1.9 as a cause of painful peripheral neuropathy. * Abbreviations : DRG : dorsal root ganglion RMP : resting membrane potential TTX : tetrodotoxin

  • the presence and role of the tetrodotoxin resistant Sodium Channel Nav1.9 nan in nociceptive primary afferent neurons
    The Journal of Neuroscience, 2002
    Co-Authors: Xin Fang, Sulayman D Dibhajj, Stephen G Waxman, Laiche Djouhri, Joel A Black, Sally N Lawson
    Abstract:

    This is the first examination of sensory receptive properties and associated electrophysiological properties in vivo of dorsal root ganglion (DRG) neurons that express the TTX-resistant Sodium Channel Nav1.9 (NaN). Intracellular recordings in lumbar DRGs in Wistar rats enabled units with dorsal root C-, Aδ-, or Aα/β-fibers to be classified as nociceptive, low-threshold mechanoreceptive (LTM), or unresponsive. Intracellular dye injection enabled subsequent immunocytochemistry for Nav1.9-like immunoreactivity (Nav1.9-LI). Nav1.9-LI was expressed selectively in nociceptive-type (C- and A-fiber nociceptive and C-unresponsive) units. Of the nociceptive units, 64, 54, and 31% of C-, Aδ-, and Aα/β-fiber units, respectively, were positive for Nav1.9-LI. C-unresponsive units were included in the nociceptive-type group on the basis of their nociceptor-like membrane properties; 91% were positive. Nav1.9-LI was undetectable in Aδ- or Aα/β-fiber LTM units and in one C-LTM unit. Nav1.9-LI intensity was correlated negatively with soma size and conduction velocity in nociceptive units and with conduction velocity in C-fiber units. There was a positive correlation with action potential rise time in nociceptive-type units with membrane potentials equal to or more negative than –50 mV. The data provide direct evidence that Nav1.9 is expressed selectively in (but not in all) C- and A-fiber nociceptive-type units and suggest that Nav1.9 contributes to membrane properties that are typical of nociceptive neurons.

Carolina Gomisperez - One of the best experts on this subject based on the ideXlab platform.

  • a 49 residue sequence motif in the c terminus of Nav1.9 regulates trafficking of the Channel to the plasma membrane
    Journal of Biological Chemistry, 2020
    Co-Authors: Daria V Sizova, Carolina Gomisperez, Stephen G Waxman, Mark Estacion, Elizabeth J. Akin, Jianying Huang, Sulayman D Dibhajj
    Abstract:

    : Genetic and functional studies have confirmed an important role for the voltage-gated Sodium Channel Nav1.9 in human pain disorders. However, low functional expression of Nav1.9 in heterologous systems, for example in human embryonic kidney 293 (HEK293) cells, has hampered studies of its biophysical and pharmacological properties, and the development of high-throughput assays for drug development targeting this Channel. The mechanistic basis for the low level of Nav1.9 currents in heterologous expression systems is not understood. Here, we implemented a multidisciplinary approach to investigate the mechanisms that govern functional Nav1.9 expression. Recombinant expression of a series of Nav1.9-Nav1.7 C-terminal chimeras in HEK293 cells identified a 49-amino-acid-long motif in the C-terminus of the two Channels that regulates expression levels of these chimeras. We confirmed the critical role of this motif in the context of a full-length Channel chimera, Nav1.9-Ct49aaNav1.7, which displayed significantly increased current density in HEK293 cells while largely retaining the characteristic Nav1.9-gating properties. High-resolution live microscopy indicated that the newly identified C-terminal motif dramatically increases the number of Channels on the plasma membrane of HEK293 cells. Molecular modeling results suggested that this motif is exposed on the cytoplasmic face of the folded C-terminus where it might interact with other Channel partners. These findings reveal that a 49-residue-long motif in Nav1.9 regulates Channel trafficking to the plasma membrane.

  • a 49 residue sequence motif in the c terminus of Nav1.9 regulates trafficking of the Channel to the plasma membrane
    Journal of Biological Chemistry, 2020
    Co-Authors: Carolina Gomisperez, Mark Estacion, Elizabeth J. Akin, Jianying Huang, Daria Sizova
    Abstract:

    Genetic and functional studies have confirmed an important role for the voltage-gated Sodium Channel Nav1.9 in human pain disorders. However, low functional expression of Nav1.9 in heterologous systems (e.g. in human embryonic kidney 293 (HEK293) cells) has hampered studies of its biophysical and pharmacological properties and the development of high-throughput assays for drug development targeting this Channel. The mechanistic basis for the low level of Nav1.9 currents in heterologous expression systems is not understood. Here, we implemented a multidisciplinary approach to investigate the mechanisms that govern functional Nav1.9 expression. Recombinant expression of a series of Nav1.9-Nav1.7 C-terminal chimeras in HEK293 cells identified a 49-amino-acid-long motif in the C terminus of the two Channels that regulates expression levels of these chimeras. We confirmed the critical role of this motif in the context of a full-length Channel chimera, Nav1.9-Ct49aaNav1.7, which displayed significantly increased current density in HEK293 cells while largely retaining the characteristic Nav1.9-gating properties. High-resolution live microscopy indicated that the newly identified C-terminal motif dramatically increases the number of Channels on the plasma membrane of HEK293 cells. Molecular modeling results suggested that this motif is exposed on the cytoplasmic face of the folded C terminus, where it might interact with other Channel partners. These findings reveal that a 49-residue-long motif in Nav1.9 regulates Channel trafficking to the plasma membrane.

Jianying Huang - One of the best experts on this subject based on the ideXlab platform.

  • a 49 residue sequence motif in the c terminus of Nav1.9 regulates trafficking of the Channel to the plasma membrane
    Journal of Biological Chemistry, 2020
    Co-Authors: Daria V Sizova, Carolina Gomisperez, Stephen G Waxman, Mark Estacion, Elizabeth J. Akin, Jianying Huang, Sulayman D Dibhajj
    Abstract:

    : Genetic and functional studies have confirmed an important role for the voltage-gated Sodium Channel Nav1.9 in human pain disorders. However, low functional expression of Nav1.9 in heterologous systems, for example in human embryonic kidney 293 (HEK293) cells, has hampered studies of its biophysical and pharmacological properties, and the development of high-throughput assays for drug development targeting this Channel. The mechanistic basis for the low level of Nav1.9 currents in heterologous expression systems is not understood. Here, we implemented a multidisciplinary approach to investigate the mechanisms that govern functional Nav1.9 expression. Recombinant expression of a series of Nav1.9-Nav1.7 C-terminal chimeras in HEK293 cells identified a 49-amino-acid-long motif in the C-terminus of the two Channels that regulates expression levels of these chimeras. We confirmed the critical role of this motif in the context of a full-length Channel chimera, Nav1.9-Ct49aaNav1.7, which displayed significantly increased current density in HEK293 cells while largely retaining the characteristic Nav1.9-gating properties. High-resolution live microscopy indicated that the newly identified C-terminal motif dramatically increases the number of Channels on the plasma membrane of HEK293 cells. Molecular modeling results suggested that this motif is exposed on the cytoplasmic face of the folded C-terminus where it might interact with other Channel partners. These findings reveal that a 49-residue-long motif in Nav1.9 regulates Channel trafficking to the plasma membrane.

  • a 49 residue sequence motif in the c terminus of Nav1.9 regulates trafficking of the Channel to the plasma membrane
    Journal of Biological Chemistry, 2020
    Co-Authors: Carolina Gomisperez, Mark Estacion, Elizabeth J. Akin, Jianying Huang, Daria Sizova
    Abstract:

    Genetic and functional studies have confirmed an important role for the voltage-gated Sodium Channel Nav1.9 in human pain disorders. However, low functional expression of Nav1.9 in heterologous systems (e.g. in human embryonic kidney 293 (HEK293) cells) has hampered studies of its biophysical and pharmacological properties and the development of high-throughput assays for drug development targeting this Channel. The mechanistic basis for the low level of Nav1.9 currents in heterologous expression systems is not understood. Here, we implemented a multidisciplinary approach to investigate the mechanisms that govern functional Nav1.9 expression. Recombinant expression of a series of Nav1.9-Nav1.7 C-terminal chimeras in HEK293 cells identified a 49-amino-acid-long motif in the C terminus of the two Channels that regulates expression levels of these chimeras. We confirmed the critical role of this motif in the context of a full-length Channel chimera, Nav1.9-Ct49aaNav1.7, which displayed significantly increased current density in HEK293 cells while largely retaining the characteristic Nav1.9-gating properties. High-resolution live microscopy indicated that the newly identified C-terminal motif dramatically increases the number of Channels on the plasma membrane of HEK293 cells. Molecular modeling results suggested that this motif is exposed on the cytoplasmic face of the folded C terminus, where it might interact with other Channel partners. These findings reveal that a 49-residue-long motif in Nav1.9 regulates Channel trafficking to the plasma membrane.

  • gain of function mutations in Sodium Channel na v 1 9 in painful neuropathy
    Brain, 2014
    Co-Authors: Jianying Huang, Mark Estacion, Monique M Gerrits, Giuseppe Lauria, Chongyang Han, Dymtro Vasylyev, Janneke G J Hoeijmakers, Lynda Tyrrell, Catharina G Faber, Sulayman D Dibhajj
    Abstract:

    Sodium Channel Nav1.9 is expressed in peripheral nociceptive neurons, as well as visceral afferents, and has been shown to act as a threshold Channel. Painful peripheral neuropathy represents a significant public health challenge and may involve gain-of-function variants in Sodium Channels that are preferentially expressed in peripheral sensory neurons. Although gain-of-function variants of peripheral Sodium Channels Nav1.7 and Nav1.8 have recently been found in painful small fibre neuropathy, the aetiology of peripheral neuropathy in many cases remains unknown. We evaluated 459 patients who were referred for possible painful peripheral neuropathy, and confirmed the diagnosis of small fibre neuropathy in a cohort of 393 patients (369 patients with pure small fibre neuropathy, and small fibre neuropathy together with large fibre involvement in an additional 24 patients). From this cohort of 393 patients with peripheral neuropathy, we sequenced SCN11A in 345 patients without mutations in SCN9A and SCN10A , and found eight variants in 12 patients. Functional profiling by electrophysiological recordings showed that these Nav1.9 mutations confer gain-of-function attributes to the Channel, depolarize resting membrane potential of dorsal root ganglion neurons, enhance spontaneous firing, and increase evoked firing of these neurons. Our data show, for the first time, missense mutations of Nav1.9 in individuals with painful peripheral neuropathy. These genetic and functional observations identify missense mutations of Nav1.9 as a cause of painful peripheral neuropathy. * Abbreviations : DRG : dorsal root ganglion RMP : resting membrane potential TTX : tetrodotoxin

Stephen G Waxman - One of the best experts on this subject based on the ideXlab platform.

  • a 49 residue sequence motif in the c terminus of Nav1.9 regulates trafficking of the Channel to the plasma membrane
    Journal of Biological Chemistry, 2020
    Co-Authors: Daria V Sizova, Carolina Gomisperez, Stephen G Waxman, Mark Estacion, Elizabeth J. Akin, Jianying Huang, Sulayman D Dibhajj
    Abstract:

    : Genetic and functional studies have confirmed an important role for the voltage-gated Sodium Channel Nav1.9 in human pain disorders. However, low functional expression of Nav1.9 in heterologous systems, for example in human embryonic kidney 293 (HEK293) cells, has hampered studies of its biophysical and pharmacological properties, and the development of high-throughput assays for drug development targeting this Channel. The mechanistic basis for the low level of Nav1.9 currents in heterologous expression systems is not understood. Here, we implemented a multidisciplinary approach to investigate the mechanisms that govern functional Nav1.9 expression. Recombinant expression of a series of Nav1.9-Nav1.7 C-terminal chimeras in HEK293 cells identified a 49-amino-acid-long motif in the C-terminus of the two Channels that regulates expression levels of these chimeras. We confirmed the critical role of this motif in the context of a full-length Channel chimera, Nav1.9-Ct49aaNav1.7, which displayed significantly increased current density in HEK293 cells while largely retaining the characteristic Nav1.9-gating properties. High-resolution live microscopy indicated that the newly identified C-terminal motif dramatically increases the number of Channels on the plasma membrane of HEK293 cells. Molecular modeling results suggested that this motif is exposed on the cytoplasmic face of the folded C-terminus where it might interact with other Channel partners. These findings reveal that a 49-residue-long motif in Nav1.9 regulates Channel trafficking to the plasma membrane.

  • Sodium Channel genes in pain related disorders phenotype genotype associations and recommendations for clinical use
    Lancet Neurology, 2014
    Co-Authors: Sulayman D Dibhajj, Stephen G Waxman, Ingemar S J Merkies, Monique M Gerrits, Giuseppe Lauria, James J Cox, J Wood, Geoffrey C Woods
    Abstract:

    Human studies have firmly implicated voltage-gated Sodium Channels in human pain disorders, and targeted and massively parallel genomic sequencing is beginning to be used in clinical practice to determine which Sodium Channel variants are involved. Missense substitutions of SCN9A, the gene encoding Sodium Channel NaV1.7, SCN10A, the gene encoding Sodium Channel NaV1.8, and SCN11A, the gene encoding Sodium Channel Nav1.9, produce gain-of-function changes that contribute to pain in many human painful disorders. Genomic sequencing might help to establish a diagnosis, and in the future might support individualisation of therapeutic approaches. However, in many cases, and especially in Sodium Channelopathies, the results from genomic sequencing can only be appropriately interpreted in the context of an extensive functional assessment, or family segregation analysis of phenotype and genotype.

  • pge2 increases the tetrodotoxin resistant Nav1.9 Sodium current in mouse drg neurons via g proteins
    Brain Research, 2004
    Co-Authors: Anthony M Rush, Stephen G Waxman
    Abstract:

    Inflammation caused by tissue damage results in pain, reflecting an increase in excitability of the primary afferent neurons innervating the area. There is some evidence to suggest that altered function of voltage-gated Sodium Channels is responsible for the hyperexcitability produced by inflammatory agents, possibly acting through G-proteins, but the role of different Channel subtypes has not been fully explored. The tetrodotoxin-resistant (TTX-R) Sodium Channel Nav1.9 is expressed selectively in C- and A-fibre nociceptive-type units and is upregulated by G-protein activation. In this study, we examined the effects of the inflammatory agent prostaglandin-E2 (PGE2) on Nav1.9 current in both Nav1.8-null and wild-type (WT) mice and explored the role of specific G-proteins in modulation. PGE2 caused a twofold increase in Nav1.9 current (p<0.05) in both systems. Steady-state activation was shifted in a hyperpolarizing direction by 6–8 mV and availability of Channels by 12 mV. No differences in the activation and inactivation kinetics could be detected. The increase in current was blocked by pertussis toxin (PTX) but not cholera toxin (CTX), showing involvement of Gi/o but not Gs subunits. Our data indicate that Nav1.9 current can be increased during inflammation via a G-protein dependent mechanism and suggest that this could contribute to the regulation of electrogenesis in dorsal root ganglia (DRG) neurons.

  • the presence and role of the tetrodotoxin resistant Sodium Channel Nav1.9 nan in nociceptive primary afferent neurons
    The Journal of Neuroscience, 2002
    Co-Authors: Xin Fang, Sulayman D Dibhajj, Stephen G Waxman, Laiche Djouhri, Joel A Black, Sally N Lawson
    Abstract:

    This is the first examination of sensory receptive properties and associated electrophysiological properties in vivo of dorsal root ganglion (DRG) neurons that express the TTX-resistant Sodium Channel Nav1.9 (NaN). Intracellular recordings in lumbar DRGs in Wistar rats enabled units with dorsal root C-, Aδ-, or Aα/β-fibers to be classified as nociceptive, low-threshold mechanoreceptive (LTM), or unresponsive. Intracellular dye injection enabled subsequent immunocytochemistry for Nav1.9-like immunoreactivity (Nav1.9-LI). Nav1.9-LI was expressed selectively in nociceptive-type (C- and A-fiber nociceptive and C-unresponsive) units. Of the nociceptive units, 64, 54, and 31% of C-, Aδ-, and Aα/β-fiber units, respectively, were positive for Nav1.9-LI. C-unresponsive units were included in the nociceptive-type group on the basis of their nociceptor-like membrane properties; 91% were positive. Nav1.9-LI was undetectable in Aδ- or Aα/β-fiber LTM units and in one C-LTM unit. Nav1.9-LI intensity was correlated negatively with soma size and conduction velocity in nociceptive units and with conduction velocity in C-fiber units. There was a positive correlation with action potential rise time in nociceptive-type units with membrane potentials equal to or more negative than –50 mV. The data provide direct evidence that Nav1.9 is expressed selectively in (but not in all) C- and A-fiber nociceptive-type units and suggest that Nav1.9 contributes to membrane properties that are typical of nociceptive neurons.

Mark Estacion - One of the best experts on this subject based on the ideXlab platform.

  • a 49 residue sequence motif in the c terminus of Nav1.9 regulates trafficking of the Channel to the plasma membrane
    Journal of Biological Chemistry, 2020
    Co-Authors: Daria V Sizova, Carolina Gomisperez, Stephen G Waxman, Mark Estacion, Elizabeth J. Akin, Jianying Huang, Sulayman D Dibhajj
    Abstract:

    : Genetic and functional studies have confirmed an important role for the voltage-gated Sodium Channel Nav1.9 in human pain disorders. However, low functional expression of Nav1.9 in heterologous systems, for example in human embryonic kidney 293 (HEK293) cells, has hampered studies of its biophysical and pharmacological properties, and the development of high-throughput assays for drug development targeting this Channel. The mechanistic basis for the low level of Nav1.9 currents in heterologous expression systems is not understood. Here, we implemented a multidisciplinary approach to investigate the mechanisms that govern functional Nav1.9 expression. Recombinant expression of a series of Nav1.9-Nav1.7 C-terminal chimeras in HEK293 cells identified a 49-amino-acid-long motif in the C-terminus of the two Channels that regulates expression levels of these chimeras. We confirmed the critical role of this motif in the context of a full-length Channel chimera, Nav1.9-Ct49aaNav1.7, which displayed significantly increased current density in HEK293 cells while largely retaining the characteristic Nav1.9-gating properties. High-resolution live microscopy indicated that the newly identified C-terminal motif dramatically increases the number of Channels on the plasma membrane of HEK293 cells. Molecular modeling results suggested that this motif is exposed on the cytoplasmic face of the folded C-terminus where it might interact with other Channel partners. These findings reveal that a 49-residue-long motif in Nav1.9 regulates Channel trafficking to the plasma membrane.

  • a 49 residue sequence motif in the c terminus of Nav1.9 regulates trafficking of the Channel to the plasma membrane
    Journal of Biological Chemistry, 2020
    Co-Authors: Carolina Gomisperez, Mark Estacion, Elizabeth J. Akin, Jianying Huang, Daria Sizova
    Abstract:

    Genetic and functional studies have confirmed an important role for the voltage-gated Sodium Channel Nav1.9 in human pain disorders. However, low functional expression of Nav1.9 in heterologous systems (e.g. in human embryonic kidney 293 (HEK293) cells) has hampered studies of its biophysical and pharmacological properties and the development of high-throughput assays for drug development targeting this Channel. The mechanistic basis for the low level of Nav1.9 currents in heterologous expression systems is not understood. Here, we implemented a multidisciplinary approach to investigate the mechanisms that govern functional Nav1.9 expression. Recombinant expression of a series of Nav1.9-Nav1.7 C-terminal chimeras in HEK293 cells identified a 49-amino-acid-long motif in the C terminus of the two Channels that regulates expression levels of these chimeras. We confirmed the critical role of this motif in the context of a full-length Channel chimera, Nav1.9-Ct49aaNav1.7, which displayed significantly increased current density in HEK293 cells while largely retaining the characteristic Nav1.9-gating properties. High-resolution live microscopy indicated that the newly identified C-terminal motif dramatically increases the number of Channels on the plasma membrane of HEK293 cells. Molecular modeling results suggested that this motif is exposed on the cytoplasmic face of the folded C terminus, where it might interact with other Channel partners. These findings reveal that a 49-residue-long motif in Nav1.9 regulates Channel trafficking to the plasma membrane.

  • gain of function mutations in Sodium Channel na v 1 9 in painful neuropathy
    Brain, 2014
    Co-Authors: Jianying Huang, Mark Estacion, Monique M Gerrits, Giuseppe Lauria, Chongyang Han, Dymtro Vasylyev, Janneke G J Hoeijmakers, Lynda Tyrrell, Catharina G Faber, Sulayman D Dibhajj
    Abstract:

    Sodium Channel Nav1.9 is expressed in peripheral nociceptive neurons, as well as visceral afferents, and has been shown to act as a threshold Channel. Painful peripheral neuropathy represents a significant public health challenge and may involve gain-of-function variants in Sodium Channels that are preferentially expressed in peripheral sensory neurons. Although gain-of-function variants of peripheral Sodium Channels Nav1.7 and Nav1.8 have recently been found in painful small fibre neuropathy, the aetiology of peripheral neuropathy in many cases remains unknown. We evaluated 459 patients who were referred for possible painful peripheral neuropathy, and confirmed the diagnosis of small fibre neuropathy in a cohort of 393 patients (369 patients with pure small fibre neuropathy, and small fibre neuropathy together with large fibre involvement in an additional 24 patients). From this cohort of 393 patients with peripheral neuropathy, we sequenced SCN11A in 345 patients without mutations in SCN9A and SCN10A , and found eight variants in 12 patients. Functional profiling by electrophysiological recordings showed that these Nav1.9 mutations confer gain-of-function attributes to the Channel, depolarize resting membrane potential of dorsal root ganglion neurons, enhance spontaneous firing, and increase evoked firing of these neurons. Our data show, for the first time, missense mutations of Nav1.9 in individuals with painful peripheral neuropathy. These genetic and functional observations identify missense mutations of Nav1.9 as a cause of painful peripheral neuropathy. * Abbreviations : DRG : dorsal root ganglion RMP : resting membrane potential TTX : tetrodotoxin