Gain-of-function mutation in SCN11A causes itch and affects neurogenic inflammation and muscle function in Scn11a(+/L799P) mice

Mutations in the genes encoding for voltage-gated sodium channels cause profound sensory disturbances and other symptoms dependent on the distribution of a particular channel subtype in different organs. Humans with the gain-of-function mutation p.Leu811Pro in SCN11A (encoding for the voltage-gated Na(v)1.9 channel) exhibit congenital insensitivity to pain, pruritus, self-inflicted injuries, slow healing wounds, muscle weakness, Charcot-like arthropathies, and intestinal dysmotility. As already shown, knock-in mice (Scn11a(+/L799P)) carrying the orthologous mutation p.Leu799Pro replicate reduced pain sensitivity and show frequent tissue lesions. In the present study we explored whether Scn11a(+/L799P) mice develop also pruritus, muscle weakness, and changes in gastrointestinal transit time. Furthermore, we analyzed morphological and functional differences in nerves, skeletal muscle, joints and small intestine from Scn11a(+/L799P) and Scn11a(+/+) wild type mice. Compared to Scn11a(+/+) mice, Scn11a(+/L799P) mice showed enhanced scratching bouts before skin lesions developed, indicating pruritus. Scn11a(+/L799P) mice exhibited reduced grip strength, but no disturbances in motor coordination. Skeletal muscle fiber types and joint architecture were unaltered in Scn11a(+/L799P) mice. Their gastrointestinal transit time was unaltered. The small intestine from Scn11a(+/L799P) showed a small shift towards less frequent peristaltic movements. Similar proportions of lumbar dorsal root ganglion neurons from Scn11a(+/L799P) and Scn11a(+/+) mice were calcitonin gene-related peptide (CGRP-) positive, but isolated sciatic nerves from Scn11a(+/L799P) mice exhibited a significant reduction of the capsaicin-evoked release of CGRP indicating reduced neurogenic inflammation. These data indicate important Na(v)1.9 channel functions in several organs in both humans and mice. They support the pathophysiological relevance of increased basal activity of Na(v)1.9 channels for sensory abnormalities (pain and itch) and suggest resulting malfunctions of the motor system and of the gastrointestinal tract. Scn11a(+/L799P) mice are suitable to investigate the role of Na(v)1.9, and to explore the pathophysiological changes and mechanisms which develop as a consequence of Na(v)1.9 hyperactivity.