The X-linked form of Charcot–Marie–Tooth disease (CMTX) is caused
by mutations in connexin32 (Cx32), a gap junction protein expressed by
Schwann cells where it forms reflexive channels that allow the passage of
ions and signaling molecules across the myelin sheath. Although most
mutations result in loss of function, several studies have reported that
some retain the ability to form homotypic intercellular channels. To gain
insight into the molecular defect of three functional CMTX variants,
S26L, D111 – 116 and R220stop, we have used several fluorescent tracers
of different size and ionic charge to compare their permeation properties
to those of wild-type Cx32. Although all mutations allowed the passage of
the dye with the smallest molecular mass, they exhibited a clear
reduction in the permeability of either one or all of the probes with
respect to wild-type channels, as assessed by the percentage of injections
showing dye coupling. These data reveal that a lower size cutoff
distinguishes these functional CMTX variants from wild-type channels
and suggest that this defect may be of pathophysiological relevance.
