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Congenital Insensitivity to Pain: Novel SCN9A Missense and In-Frame Deletion Mutations
Authors
Marco Baralle
James J Cox
+10 more
Jacov Levy
Esther Manor
Adeline K Nicholas
Ruti Parvari
Frank Reimann
Jony Sheynin
Zamir Shorer
C Geoffery Woods
Elizabeth Wraige
Lorena Zubovic
Publication date
15 July 2010
Publisher
Wiley Subscription Services, Inc., A Wiley Company
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PubMed
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
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info:doi/10.1002%2Fhumu.21325
Last time updated on 01/04/2019