The COL6A5-p.Glu2272* mutation induces chronic itch in mice

Abstract Pruritus is a common irritating sensation that provokes the desire to scratch. Environmental and genetic factors, altering barrier skin dysfunction, or hypersensitivity of sensory nerves, contribute to the onset of pruritus. However, the itch can become a major burden when it becomes chronic, like in neuropathic itch. The rare Collagen VI alpha 5 ( COL6A5 ) gene variant p.Glu2272* was recently identified in two families and an independent patient with chronic neuropathic itch. These patients showed reduced COL6A5 expression in the skin and normal skin morphology. However, little progress has been made until now toward understanding the relationships between this mutation and chronic itch. Therefore, we developed the first mouse model that recapitulates COL6A5- p.Glu2272* mutation using the CRISPR-Cas technology and characterized this new mouse model. The mutant mRNA, measured by RT-ddPCR, was expressed at normal levels in dorsal root ganglia and decreased in skin. The functional exploration showed changes in the behavior of control individuals kept with mutant carriers and confirmed the effect in the mutant mice with some sex dysmorphology. Spontaneous scratching was detected in male and female mutants, with increased anxiety-like behavior in female mutants and despair-like behavior in sex-grouped mutants. These results suggest that the COL6A5- p.Glu2272* mutation found in patients contributes to chronic itch and probably induces additional behavioral changes. The COL6A5 -p.Glu2272* mouse model could elucidate the pathophysiological mechanisms underlying COL6A5 role in neuropathic itch and help identify potential new therapeutic targets.