Abstract
We identified and clinically investigated two patients with primary erythromelalgia mutations (PEM), which are the first reported to map to the fourth domain of Nav1.7 (DIV). The identified mutations (A1746G and W1538R) were cloned and transfected to cell cultures followed by electrophysiological analysis in whole-cell configuration. The investigated patients presented with PEM, while age of onset was very different (3 vs. 61 years of age). Electrophysiological characterization revealed that the early onset A1746G mutation leads to a marked hyperpolarizing shift in voltage dependence of steady-state activation, larger window currents, faster activation kinetics (time-to-peak current) and recovery from steady-state inactivation compared to wild-type Nav1.7, indicating a pronounced gain-of-function. Furthermore, we found a hyperpolarizing shift in voltage dependence of slow inactivation, which is another feature commonly found in Nav1.7 mutations associated with PEM. In silico neuron simulation revealed reduced firing thresholds and increased repetitive firing, both indicating hyperexcitability. The late-onset W1538R mutation also revealed gain-of-function properties, although to a lesser extent. Our findings demonstrate that mutations encoding for DIV of Nav1.7 can not only be linked to congenital insensitivity to pain or paroxysmal extreme pain disorder but can also be causative of PEM, if voltage dependency of channel activation is affected. This supports the view that the degree of biophysical property changes caused by a mutation may have an impact on age of clinical manifestation of PEM. In summary, these findings extent the genotype–phenotype correlation profile for SCN9A and highlight a new region of Nav1.7 that is implicated in PEM.Electronic supplementary materialThe online version of this article (doi:10.1007/s12017-012-8216-8) contains supplementary material, which is available to authorized users.
Highlights
Recent studies have confirmed a pivotal role for the Nav1.7 voltage-gated sodium channel in human familial gainof-function (Yang et al 2004; Fertleman et al 2006) and loss-of-function pain syndromes (Cox et al 2006)
We identified and clinically investigated two patients with primary erythromelalgia mutations (PEM), which are the first reported to map to the fourth domain of Nav1.7 (DIV)
Recessive loss-of-function mutations in SCN9A result in congenital insensitivity to pain (CIP), whereas gainof-function, dominant mutations lead to sensory neuronal hyperexcitability and the development of painful phenotypes described as inherited or primary erythromelalgia (PEM or IEM) (Yang et al 2004; Dib-Hajj et al 2005) and paroxysmal extreme pain disorder (PEPD) (Fertleman et al 2006; Choi et al 2011)
Summary
Recent studies have confirmed a pivotal role for the Nav1.7 voltage-gated sodium channel in human familial gainof-function (Yang et al 2004; Fertleman et al 2006) and loss-of-function pain syndromes (Cox et al 2006). Recessive loss-of-function mutations in SCN9A result in congenital insensitivity to pain (CIP), whereas gainof-function, dominant mutations lead to sensory neuronal hyperexcitability and the development of painful phenotypes described as inherited or primary erythromelalgia (PEM or IEM) (Yang et al 2004; Dib-Hajj et al 2005) and paroxysmal extreme pain disorder (PEPD) (Fertleman et al 2006; Choi et al 2011). Further elucidation of the connection between single-point mutations in SCN9A encoding for Nav1.7 gain-of-function mutations, impact on biophysical channel properties, disease onset and clinical symptoms may contribute to our understanding of this debilitating disease, and enable us to interpret results from genetic testing more rationally and to develop a causative treatment
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