Trends in Molecular Medicine
ReviewPainful Na-channelopathies: an expanding universe
Section snippets
Inherited erythromelalgia and paroxysmal extreme pain disorder
Inherited erythromelalgia (IEM), the first painful Na-channelopathy to be identified, is a rare genetic disorder in which affected individuals experience searing, burning pain (usually in the distal extremities) in response to mild warmth. Following linkage studies that implicated a locus (2q 31–32) in chromosome 2 [3], data from two families with IEM identified point mutations in the SCN9A gene that encodes the NaV1.7 sodium channel [4]. Functional profiling of these IEM mutations demonstrated
Channelopathy-associated insensitivity to pain
Shortly after gain-of-function mutations in NaV1.7 were described in the context of IEM, a rare loss-of-function disorder due to the absence of functional NaV1.7 channels was described in human subjects 11, 12, 13. Channelopathy-associated insensitivity to pain (CIP), caused by null mutations in SCN9A, is clinically characterized by an inability to sense noxious stimuli or events as painful; affected individuals experience painless injuries, such as fractures or burns, and undergo dental
NaV1.7 mutations and painful peripheral neuropathy
IEM, PEPD, and CIP are an ensemble of rare genetic ‘model diseases’ that establish a strong link between NaV1.7 and human pain at both the gain-of-function and loss-of-function levels. More recent studies have established a link between NaV1.7, NaV1.8, and pain in a common painful disorder, painful peripheral neuropathy. Small fiber neuropathy is a form of painful neuropathy that is characterized by autonomic dysfunction and severe pain, usually in a distal ‘stocking-and-glove’ pattern [18].
NaV1.8 mutations and painful peripheral neuropathy
Recently, analysis of the SCN10A gene, which encodes the NaV1.8 sodium channel, revealed seven NaV1.8 mutations in nine subjects from a series of 104 patients with painful, predominantly small fiber neuropathy who did not carry mutations in SCN9A [21]. Three mutations met the criteria for potential pathogenicity based on predictive algorithms; two of these three mutations enhanced the response of the channels to depolarization and produced hyperexcitability of DRG neurons. This observation
Genotype–phenotype correlations
Even within a relatively discrete diagnostic category, such as IEM or small fiber neuropathy, there can be differences in clinical presentations for patients harboring different mutations. Most patients with IEM, for example, manifest pain beginning very early in life, during infancy or early childhood, but occasional patients display late onset of pain. The age of pain onset appears, in at least some cases, to be related to the degree of activation enhancement 22, 23, but there is also
Acquired changes in channel expression and pain
Evidence also exists for a broader link between these sodium channels and human pain. Estacion et al. [26] characterized a single nucleotide polymorphism in SCN9A, present in approximately 30% of the control population, that modestly increases DRG neuron excitability and suggested that this polymorphism might bias sensitivity to pain. Subsequently reported genetic association studies found a correlation between expression of the minor (hyperexcitability associated) allele and increased pain
Pharmacogenomics
Finally, advances in structural modeling have facilitated progress in pharmacogenomics. Capitalizing on the recently solved crystal structure of bacterial sodium channels [29], Yang et al. [30] constructed an atomic level structural model of the human NaV1.7 channel and used this to predict channel pharmacoresponsiveness in the context of various mutations. Beginning with a previously described IEM mutation [31] that, in addition to producing disease, endows the mutant channel with enhanced
Open questions and future directions
The universe of painful Na-channelopathies has expanded from rare genetic model disorders to more commonly observed diseases, and the underlying causes now include both NaV1.7 and NaV1.8 (Table 1). Additional painful channelopathies may exist, but how should their causes be identified? Large kindred analysis may provide compelling information, and genome-wide association studies may also yield important insights, although these studies require large numbers of patients and may not, in
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