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A new mutation in GJC2 associated with subclinical leukodystrophy.

Research paper by Charles K CK Abrams, Steven S SS Scherer, Rafael R Flores-Obando, Mona M MM Freidin, Sarah S Wong, Eleonora E Lamantea, Laura L Farina, Vidmer V Scaioli, Davide D Pareyson, Ettore E Salsano

Indexed on: 26 Jul '14Published on: 26 Jul '14Published in: Journal of Neurology



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.