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Sporadic onset of erythermalgia: A gain-of-function mutation in Nav1.7

Authors

  • Chongyang Han BS,

    1. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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    • C.H. and A.M.R contributed equally to this study.

  • Anthony M. Rush PhD,

    1. Department of Neurology, Yale University School of Medicine, New Haven
    2. Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven
    3. Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT
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    • C.H. and A.M.R contributed equally to this study.

  • Sulayman D. Dib-Hajj PhD,

    1. Department of Neurology, Yale University School of Medicine, New Haven
    2. Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven
    3. Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT
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  • Song Li MD, PhD,

    1. Department of Dermatology, Peking University First Hospital, Beijing, China
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  • Zhe Xu MD,

    1. Department of Dermatology, Beijing Children Hospital, Beijing, China
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  • Yun Wang MD, PhD,

    1. Department of Dermatology, Peking University First Hospital, Beijing, China
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  • Lynda Tyrrell MS,

    1. Department of Neurology, Yale University School of Medicine, New Haven
    2. Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven
    3. Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT
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  • Xiaoliang Wang PhD,

    1. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Yong Yang MD, PhD,

    Corresponding author
    1. Department of Dermatology, Peking University First Hospital, Beijing, China
    • Department of Dermatology, Peking University First Hospital, No. 8. Xish-iku Street, Xicheng District, Beijing, 10034, China
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  • Stephen G. Waxman MD, PhD

    Corresponding author
    1. Department of Neurology, Yale University School of Medicine, New Haven
    2. Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven
    3. Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT
    • Department of Neurology, LCI 707, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510
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Abstract

Objective

Inherited erythermalgia (erythromelalgia) is an autosomal dominant disorder in which patients experience severe burning pain in the extremities, in response to mild thermal stimuli and exercise. Although mutations in sodium channel Nav1.7 have been shown to underlie erythermalgia in several multigeneration families with the disease that have been investigated to date, the molecular basis of erythermalgia in sporadic cases is enigmatic. We investigated the role of Nav1.7 in a sporadic case of erythermalgia in a Chinese family.

Methods

Genomic DNA from patients and their asymptomatic family members were sequenced to identify mutations in Nav1.7. Whole-cell patch clamp analysis was used to characterize biophysical properties of wild-type and mutant Nav1.7 channels in mammalian cells.

Results

A single amino acid substitution in the DIIS4-S5 linker of Nav1.7 was present in two children whose parents were asymptomatic. The asymptomatic father was genetically mosaic for the mutation. This mutation produces a hyperpolarizing shift in channel activation and an increase in amplitude of the response to slow, small depolarizations.

Interpretation

Founder mutations in Nav1.7, which can confer hyperexcitability on peripheral sensory neurons, can underlie sporadic erythermalgia. Ann Neurol 2006

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