Peripheral temperature dysregulation associated with functionally altered NaV1.8 channels

Pflügers Archiv - European Journal of Physiology, vol. 475, pp. 1343–1355

Abstract

Abstract The voltage-gated sodium channel NaV1.8 is prominently expressed in the soma and axons of small-caliber sensory neurons, and pathogenic variants of the corresponding geneSCN10Aare associated with peripheral pain and autonomic dysfunction. While most disease-associatedSCN10Avariants confer gain-of-function properties to NaV1.8, resulting in hyperexcitability of sensory neurons, a few affect afferent excitability through a loss-of-function mechanism. Using whole-exome sequencing, we here identify a rare heterozygousSCN10Amissense variant resulting in alteration p.V1287I in NaV1.8 in a patient with a 15-year history of progressively worsening temperature dysregulation in the distal extremities, particularly in the feet. Further symptoms include increasingly intensifying tingling and numbness in the fingers and increased sweating. To assess the impact of p.V1287I on channel function, we performed voltage-clamp recordings demonstrating that the alteration confers loss- and gain-of-function characteristics to NaV1.8 characterized by a right-shifted voltage dependence of channel activation and inactivation. Current-clamp recordings from transfected mouse dorsal root ganglion neurons further revealed that NaV1.8-V1287I channels broaden the action potentials of sensory neurons and increase their firing rates in response to depolarizing current stimulations, indicating a gain-of-function mechanism of the variant at the cellular level in a heterozygous setting. The data support the hypothesis that the properties of NaV1.8 p.V1287I are causative for the patient’s symptoms and that nonpainful peripheral paresthesias should be considered part of the clinical spectrum of NaV1.8-associated disorders.

Authors 7

1. Simon Loose

   University of Lübeck

   Affiliation as printed

   Department of Anesthesiology and Intensive Care & CBBM - Center of Brain, Behavior and Metabolism, University of Luebeck, Ratzeburger Allee 160, 23562, Luebeck, Germany

   Department of Anesthesiology and Intensive Care & CBBM – Center of Brain, Behavior and Metabolism, University of Luebeck, Ratzeburger Allee 160, 23562, Luebeck, Germany

2. Annette Lischka Aachen Institute for Human Genetics and Genomic Medicine Medical Faculty

   RWTH Aachen University

   Affiliation as printed

   Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany

3. Samuel Kuehs

   University of Lübeck

   Affiliation as printed

   Department of Anesthesiology and Intensive Care & CBBM - Center of Brain, Behavior and Metabolism, University of Luebeck, Ratzeburger Allee 160, 23562, Luebeck, Germany

   Department of Anesthesiology and Intensive Care & CBBM – Center of Brain, Behavior and Metabolism, University of Luebeck, Ratzeburger Allee 160, 23562, Luebeck, Germany

4. Carla Nau

   University of Lübeck

   Affiliation as printed

   Department of Anesthesiology and Intensive Care & CBBM - Center of Brain, Behavior and Metabolism, University of Luebeck, Ratzeburger Allee 160, 23562, Luebeck, Germany

   Department of Anesthesiology and Intensive Care & CBBM – Center of Brain, Behavior and Metabolism, University of Luebeck, Ratzeburger Allee 160, 23562, Luebeck, Germany

5. Stefan H. Heinemann

   Jena University Hospital · Friedrich Schiller University Jena

   Affiliation as printed

   Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena and Jena University Hospital, Jena, Germany

6. Ingo Kurth Aachen Institute for Human Genetics and Genomic Medicine Medical Faculty

   RWTH Aachen University

   Affiliation as printed

   Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany

7. Enrico Leipold corresponding

   University of Lübeck

   Affiliation as printed

   Department of Anesthesiology and Intensive Care & CBBM - Center of Brain, Behavior and Metabolism, University of Luebeck, Ratzeburger Allee 160, 23562, Luebeck, Germany. enrico.leipold@uni-luebeck.de

   Department of Anesthesiology and Intensive Care & CBBM – Center of Brain, Behavior and Metabolism, University of Luebeck, Ratzeburger Allee 160, 23562, Luebeck, Germany