E44Q mutation in Na(V)1.7 in a patient with infantile paroxysmal knee pain: electrophysiological analysis of voltage-dependent sodium current

Gain-of-function mutations in voltage-gated sodium channels (Na(V)1.7, Na(V)1.8, and Na(V)1.9) are known causes of inherited pain disorders. Identification and functional assessment of new Na(V)1.7 mutations could help elucidate the phenotypic spectrum of Na(V)1.7 channelopathies. We identified a novel Na(V)1.7 mutation (E44Q in exon 2) that substitutes a glutamic acid residue for glutamine in the cytoplasmic N-terminus of Na(V)1.7 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(V)1.7, which is consistent with our patient's pain phenotype.