Abstract
SCN9A encodes the voltage-gated sodium channel Nav1.7, a protein highly expressed in pain-sensing neurons. Mutations in SCN9A cause three human pain disorders: bi-allelic loss of function mutations result in Channelopathy-associated Insensitivity to Pain (CIP), whereas activating mutations cause severe episodic pain in Paroxysmal Extreme Pain Disorder (PEPD) and Primary Erythermalgia (PE). To date, all mutations in SCN9A that cause a complete inability to experience pain are protein truncating and presumably lead to no protein being produced. Here, we describe the identification and functional characterization of two novel non-truncating mutations in families with CIP: a homozygously-inherited missense mutation found in a consanguineous Israeli Bedouin family (Nav1.7-R896Q) and a five amino acid in-frame deletion found in a sporadic compound heterozygote (Nav1.7-ΔR1370-L1374). Both of these mutations map to the pore region of the Nav1.7 sodium channel. Using transient transfection of PC12 cells we found a significant reduction in membrane localization of the mutant protein compared to the wild type. Furthermore, voltage clamp experiments of mutant-transfected HEK293 cells show a complete loss of function of the sodium channel, consistent with the absence of pain phenotype. In summary, this study has identified critical amino acids needed for the normal subcellular localization and function of Nav1.7. © 2010 Wiley-Liss, Inc.
Highlights
Pain is one of the most pervasive symptoms in clinical medicine; it occurs in a multitude of clinical conditions and is encountered by clinicians in every subspecialty
Since the patients belong to the population of Bedouins in the south of Israel where congenital insensitivity to pain with anhydrosis (CIPA) is prevalent we firstly excluded linkage to the TrkA gene, assuming homozygosity in which the two alleles are identical by descent, by the use of microsatellite markers adjacent to the gene
We analyzed whether the patients presented homozygosity near the SCN9A gene, which was reported to be mutated in Channelopathy-associated Insensitivity to Pain (CIP) patients [Cox et al, 2006; Goldberg et al, 2007; Ahmad et al, 2007; Nilsen et al, 2009]
Summary
Pain is one of the most pervasive symptoms in clinical medicine; it occurs in a multitude of clinical conditions and is encountered by clinicians in every subspecialty. SCN9A Loss of Function Mutations E1671 analgesic drugs and treatments with up to 50% of treated subjects receiving inadequate pain relief [Stewart et al, 2003]. In this paper we explore one method to achieve this goal: the analysis of gene mutations in humans with altered pain perception. Channelopathy-associated Insensitivity to Pain (CIP) is a rare condition in which patients have no pain perception and anosmia, but are otherwise essentially normal (MIM# 243000). Genetic studies in families demonstrating recessively inherited CIP have identified nonsense mutations that result in truncation of the voltage-gated sodium channel type IX α subunit (SCN9A), a 113.5-kb gene comprising 26 exons (MIM# 603415) [Cox et al, 2006; Goldberg et al, 2007; Ahmad et al, 2007; Nilsen et al, 2009]. Functional studies, performed for only some mutations to date, have shown that CIP-associated mutations lead to a loss of function of Nav1.7 [Cox et al, 2006]
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