Alternative splicing may contribute to time-dependent manifestation of inherited erythromelalgia

Jin Sung Choi, Xiaoyang Cheng, Edmund Foster, Andreas Leffler, Lynda Tyrrell, Rene H.M. Te Morsche, Emmanuella M. Eastman, Henry J. Jansen, Kathrin Huehne, Carla Nau, Sulayman D. Dib-Hajj, Joost P.H. Drenth, Stephen G. Waxman

    42 Citations (Scopus)

    Abstract

    The Nav1.7 sodium channel is preferentially expressed in nocioceptive dorsal root ganglion and sympathetic ganglion neurons. Gain-of-function mutations in Nav1.7 produce the nocioceptor hyperexcitability underlying inherited erythromelalgia, characterized in most kindreds by early-age onset of severe pain. Here we describe a mutation (Nav1.7-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 Nav1.7 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 Nav1.7 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.

    Original languageEnglish
    JournalBrain
    Volume133
    Issue number6
    Pages (from-to)1823-1835
    Number of pages13
    ISSN0006-8950
    DOIs
    Publication statusPublished - 06.2010

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