CMT X: Selective defects in channel permeability associated with Cx32 mutations

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Neurobiol Dis. 2006 Jan 24

Selective defects in channel permeability associated with Cx32

mutations causing X-linked Charcot-Marie-Tooth disease.

Bicego M, Morassutto S, VH, Morgutti M, Mammano F, D'

P, Bruzzone R.

Dipartimento di Biochimica, Biofisica e Chimica delle Macromolecole,

University of Trieste, via Licio Giorgieri 1, 34127 Trieste, Italy.

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, Delta111-116 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.