Alternative splicing may contribute to time-dependent manifestation of inherited erythromelalgia
| Autor: | Lynda Tyrrell, Carla Nau, Emmanuella M. Eastman, Sulayman D. Dib-Hajj, Andreas Leffler, H.J. Jansen, Edmund Foster, Xiaoyang Cheng, Stephen G. Waxman, Joost P.H. Drenth, Jin-Sung Choi, Kathrin Huehne, Rene H. M. te Morsche |
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| Rok vydání: | 2010 |
| Předmět: |
Gene isoform
Male Adolescent Mutant Pain Biology In Vitro Techniques Sodium Channels Rats Sprague-Dawley Young Adult Dorsal root ganglion Channelopathy Erythromelalgia Ganglia Spinal medicine Animals Humans Protein Isoforms Molecular gastro-enterology and hepatology [IGMD 2] Age of Onset Child Aged 80 and over Sodium channel Alternative splicing NAV1.7 Voltage-Gated Sodium Channel Middle Aged medicine.disease Sympathetic ganglion Rats Alternative Splicing medicine.anatomical_structure Phenotype Animals Newborn Female Neurology (clinical) Neuroscience |
| Zdroj: | Brain, 133, Pt 6, pp. 1823-35 Brain, 133, 1823-35 |
| ISSN: | 1460-2156 0006-8950 |
| Popis: | Contains fulltext : 88055.pdf (Publisher’s version ) (Closed access) The Na(v)1.7 sodium channel is preferentially expressed in nocioceptive dorsal root ganglion and sympathetic ganglion neurons. Gain-of-function mutations in Na(v)1.7 produce the nocioceptor hyperexcitability underlying inherited erythromelalgia, characterized in most kindreds by early-age onset of severe pain. Here we describe a mutation (Na(v)1.7-G616R) in a pedigree with adult-onset of pain in some family members. The mutation shifts the voltage-dependence of channel fast-inactivation in a depolarizing direction in the adult-long, but not in the neonatal-short splicing isoform of Na(v)1.7 in dorsal root ganglion neurons. Altered inactivation does not depend on the age of the dorsal root ganglion neurons in which the mutant is expressed. Expression of the mutant adult-long, but not the mutant neonatal-short, isoform of Na(v)1.7 renders dorsal root ganglion neurons hyperexcitable, reducing the current threshold for generation of action potentials, increasing spontaneous activity and increasing the frequency of firing in response to graded suprathreshold stimuli. This study shows that a change in relative expression of splice isoforms can contribute to time-dependent manifestation of the functional phenotype of a sodium channelopathy. 01 juni 2010 |
| Databáze: | OpenAIRE |
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