E44Q mutation in NaV1.7 in a patient with infantile paroxysmal knee pain: electrophysiological analysis of voltage-dependent sodium current

Kiichi Takahashi; Takayoshi Ohba; Yosuke Okamoto; Atsuko Noguchi; Hiroko Okuda; Hatasu Kobayashi; Kouji H Harada; Akio Koizumi; Kyoichi Ono; Tsutomu Takahashi

doi:10.1016/j.heliyon.2021.e07396

E44Q mutation in Na_V1.7 in a patient with infantile paroxysmal knee pain: electrophysiological analysis of voltage-dependent sodium current

Heliyon. 2021 Jun 24;7(6):e07396. doi: 10.1016/j.heliyon.2021.e07396. eCollection 2021 Jun.

Authors

Affiliations

¹ Department of Pediatrics, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita City, Akita, 010-8543, Japan.
² Department of Cell Physiology, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita City, Akita, 010-8543, Japan.
³ Department of Pain Pharmacogenetics, Kyoto University Graduate School of Medicine, Yoshida Konoe, Sakyo, Kyoto, 606-8501, Japan.
⁴ Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
⁵ Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Yoshida Konoe, Sakyo, Kyoto, 606-8501, Japan.
⁶ Institute of Public Health and Welfare Research, 18-13, Uzumasa Tanamori, Ukyo, Kyoto, 616-8141, Japan.

Abstract

Gain-of-function mutations in voltage-gated sodium channels (Na_V1.7, Na_V1.8, and Na_V1.9) are known causes of inherited pain disorders. Identification and functional assessment of new Na_V1.7 mutations could help elucidate the phenotypic spectrum of Na_V1.7 channelopathies. We identified a novel Na_V1.7 mutation (E44Q in exon 2) that substitutes a glutamic acid residue for glutamine in the cytoplasmic N-terminus of Na_V1.7 in a patient with paroxysmal pain attacks during childhood and his family who experienced similar pain episodes. To study the sodium channel's function, we performed electrophysiological recordings. Voltage-clamp recordings revealed that the mutation increased the amplitude of the non-inactivating component of the sodium current, which might facilitate channel opening. These data demonstrate that E44Q is a gain-of-function mutation in Na_V1.7, which is consistent with our patient's pain phenotype.

Keywords: NaV1.7; Paroxysmal pain; Patch-clamp techniques; SCN9A mutation; Voltage-gated sodium channel.