| Autor: |
Le Cann K; Institute of Physiology, RWTH Aachen University Hospital , Aachen, Germany., Meents JE; Institute of Physiology, RWTH Aachen University Hospital , Aachen, Germany., Sudha Bhagavath Eswaran V; Institute of Physiology, RWTH Aachen University Hospital , Aachen, Germany., Dohrn MF; Department of Neurology, Medical Faculty, RWTH Aachen University Hospital , Aachen, Germany., Bott R; Institute of Physiology, RWTH Aachen University Hospital , Aachen, Germany., Maier A; Department of Neurology, Medical Faculty, RWTH Aachen University Hospital , Aachen, Germany., Bialer M; Division of Clinical Metabolism of Medical Genetics and Human Genomics at Northwell Health System , New-York, United States., Hautvast P; Institute of Physiology, RWTH Aachen University Hospital , Aachen, Germany., Erickson A; Institute of Physiology, RWTH Aachen University Hospital , Aachen, Germany., Rolke R; Department for Palliative Care, Medical Faculty, RWTH Aachen University , Aachen, Germany., Rothermel M; Department of Chemosensation, AG Neuromodulation, Institute for Biology II, RWTH Aachen University , Aachen, 52074, Germany., Körner J; Institute of Physiology, RWTH Aachen University Hospital , Aachen, Germany.; Department of Anaesthesiology, Medical Faculty, RWTH Aachen University , Aachen, Germany., Kurth I; Institute of Human Genetics, Medical Faculty, RWTH Aachen University Hospital , Aachen, Germany., Lampert A; Institute of Physiology, RWTH Aachen University Hospital , Aachen, Germany. |
| Abstrakt: |
Mutations in the voltage-gated sodium channel Nav1.7 are linked to human pain. The Nav1.7/N1245S variant was described before in several patients suffering from primary erythromelalgia and/or olfactory hypersensitivity. We have identified this variant in a pain patient and a patient suffering from severe and life-threatening orthostatic hypotension. In addition, we report a female patient suffering from muscle pain and carrying the Nav1.7/E1139K variant. We tested both Nav1.7 variants by whole-cell voltage-clamp recordings in HEK293 cells, revealing a slightly enhanced current density for the N1245S variant when co-expressed with the β1 subunit. This effect was counteracted by an enhanced slow inactivation. Both variants showed similar voltage dependence of activation and steady-state fast inactivation, as well as kinetics of fast inactivation, deactivation, and use-dependency compared to WT Nav1.7. Finally, homology modeling revealed that the N1245S substitution results in different intramolecular interaction partners. Taken together, these experiments do not point to a clear pathogenic effect of either the N1245S or E1139K variant and suggest they may not be solely responsible for the patients' pain symptoms. As discussed previously for other variants, investigations in heterologous expression systems may not sufficiently mimic the pathophysiological situation in pain patients, and single nucleotide variants in other genes or modulatory proteins are necessary for these specific variants to show their effect. Our findings stress that biophysical investigations of ion channel mutations need to be evaluated with care and should preferably be supplemented with studies investigating the mutations in their context, ideally in human sensory neurons. |
