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Congenital insensitivity to pain: novel SCN9A missense and in-frame deletion mutations.
- Source :
-
Human mutation [Hum Mutat] 2010 Sep; Vol. 31 (9), pp. E1670-86. - Publication Year :
- 2010
-
Abstract
- SCN9Aencodes the voltage-gated sodium channel Na(v)1.7, 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 (Na(v)1.7-R896Q) and a five amino acid in-frame deletion found in a sporadic compound heterozygote (Na(v)1.7-DeltaR1370-L1374). Both of these mutations map to the pore region of the Na(v)1.7 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 Na(v)1.7.<br /> (Copyright 2010 Wiley-Liss, Inc.)
- Subjects :
- Animals
Cell Membrane metabolism
DNA Mutational Analysis
Electrophysiological Phenomena
Ethnicity genetics
Female
HEK293 Cells
Humans
Israel
Male
Mutant Proteins metabolism
NAV1.7 Voltage-Gated Sodium Channel
PC12 Cells
Pedigree
Rats
Transfection
United Kingdom
Mutation, Missense genetics
Pain Insensitivity, Congenital genetics
Reading Frames genetics
Sequence Deletion genetics
Sodium Channels genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1098-1004
- Volume :
- 31
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Human mutation
- Publication Type :
- Academic Journal
- Accession number :
- 20635406
- Full Text :
- https://doi.org/10.1002/humu.21325