Abstract
Recessive mutations in GJC2, the gene-encoding connexin 47 (Cx47), cause Pelizaeus–Merzbacher-like disease type 1, a severe dysmyelinating disorder. One recessive mutation (p.Ile33Met) has been associated with a much milder phenotype––hereditary spastic paraplegia type 44. Here, we present evidence that a novel Arg98Leu mutation causes an even milder phenotype––a subclinical leukodystrophy. The Arg98Leu mutant forms gap junction plaques in HeLa cells comparable to wild-type Cx47, but electrical coupling was 20-fold lower in cell pairs expressing Arg98Leu than for cell pairs expressing wild-type Cx47. On the other hand, coupling between Cx47Arg98Leu and Cx43WT expressing cells did not show such reductions. Single channel conductance and normalized steady-state junctional conductance–junctional voltage (G j–V j) relations differed only slightly from those for wild-type Cx47. Our data suggest that the minimal phenotype in this patient results from a reduced efficiency of opening of Cx47 channels between oligodendrocyte and oligodendrocyte with preserved coupling between oligodendrocyte and astrocyte, and support a partial loss of function model for the mild Cx47 associated disease phenotypes.
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Acknowledgments
This work was supported by the National Multiple Sclerosis Society (C.K.A. and S.S.S.) and National Institutes of Health (NIH) Grants: NS055284 (to S.S.S.), and NS067404 (to C.K.A.) and the Pierfranco and Luisa Mariani Foundation, Italy (E.L.).
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Abrams, C.K., Scherer, S.S., Flores-Obando, R. et al. A new mutation in GJC2 associated with subclinical leukodystrophy. J Neurol 261, 1929–1938 (2014). https://doi.org/10.1007/s00415-014-7429-1
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DOI: https://doi.org/10.1007/s00415-014-7429-1