The Potential Effect of Na v 1.8 in Autism Spectrum Disorder: Evidence From a Congenital Case With Compound Heterozygous SCN10A Mutations

Björn Heinrichs; Baowen Liu; Jin Zhang; Jannis E Meents; Kim Le; Andelain Erickson; Petra Hautvast; Xiwen Zhu; Ningbo Li; Yi Liu; Marc Spehr; Ute Habel; Markus Rothermel; Barbara Namer; Xianwei Zhang; Angelika Lampert; Guangyou Duan

doi:10.3389/fnmol.2021.709228

The Potential Effect of Na _v 1.8 in Autism Spectrum Disorder: Evidence From a Congenital Case With Compound Heterozygous SCN10A Mutations

Front Mol Neurosci. 2021 Jul 27:14:709228. doi: 10.3389/fnmol.2021.709228. eCollection 2021.

Authors

Björn Heinrichs¹, Baowen Liu^{2

3}, Jin Zhang³, Jannis E Meents¹, Kim Le⁴, Andelain Erickson¹, Petra Hautvast¹, Xiwen Zhu², Ningbo Li³, Yi Liu^{1

3}, Marc Spehr⁵, Ute Habel^{6

7}, Markus Rothermel⁸, Barbara Namer⁹, Xianwei Zhang³, Angelika Lampert¹, Guangyou Duan²

Affiliations

¹ Institute of Physiology, Uniklinik RWTH Aachen University, Aachen, Germany.
² Department of Anesthesiology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
³ Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁴ Department of Chemosensation, AG Neuromodulation, Institute for Biology II, RWTH Aachen University, Aachen, Germany.
⁵ Department of Chemosensation, Institute for Biology II, RWTH Aachen University, Aachen, Germany.
⁶ Department of Psychiatry, Psychotherapy and Psychosomatics, Uniklinik RWTH Aachen University, Aachen, Germany.
⁷ JARA-BRAIN Institute Brain Structure-Function Relationships: Decoding the Human Brain at Systemic Levels, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, Germany.
⁸ Institute for Physiology and Cell Biology, University of Veterinary Medicine, Foundation, Hanover, Germany.
⁹ Research Group Neurosciences of the Interdisciplinary Center for Clinical Research (IZKF), Faculty of Medicine, RWTH Aachen University, Aachen, Germany.

Abstract

Apart from the most prominent symptoms in Autism spectrum disorder (ASD), namely deficits in social interaction, communication and repetitive behavior, patients often show abnormal sensory reactivity to environmental stimuli. Especially potentially painful stimuli are reported to be experienced in a different way compared to healthy persons. In our present study, we identified an ASD patient carrying compound heterozygous mutations in the voltage-gated sodium channel (VGSC) Na _v 1.8, which is preferentially expressed in sensory neurons. We expressed both mutations, p.I1511M and p.R512^∗, in a heterologous expression system and investigated their biophysical properties using patch-clamp recordings. The results of these experiments reveal that the p.R512^∗ mutation renders the channel non-functional, while the p.I1511M mutation showed only minor effects on the channel's function. Behavioral experiments in a Na _v 1.8 loss-of-function mouse model additionally revealed that Na _v 1.8 may play a role in autism-like symptomatology. Our results present Na _v 1.8 as a protein potentially involved in ASD pathophysiology and may therefore offer new insights into the genetic basis of this disease.

Keywords: SCN10A/Nav1.8; autism spectrum disorder; genetic; mutation; p.I1511M; p.R512∗.