title: A new mutation in GJC2 associated with subclinical leukodystrophy.
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.
authors: Departments of Neurology and Physiology and Pharmacology, SUNY Downstate, 450 Clarkson Avenue, Brooklyn, NY, 11203, USA, charles.abrams@downstate.edu.
authors: Charles K
authors: CK
authors: Abrams
authors: Steven S
authors: SS
authors: Scherer
authors: Rafael
authors: R
authors: Flores-Obando
authors: Mona M
authors: MM
authors: Freidin
authors: Sarah
authors: S
authors: Wong
authors: Eleonora
authors: E
authors: Lamantea
authors: Laura
authors: L
authors: Farina
authors: Vidmer
authors: V
authors: Scaioli
authors: Davide
authors: D
authors: Pareyson
authors: Ettore
authors: E
authors: Salsano
mesh_terms: D000328:Adult; D001120:Arginine / Q000235:genetics; D001921:Brain / Q000473:pathology; D002461:Cell Line, Transformed; D017630:Connexins / Q000235:genetics*; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D005074:Evoked Potentials, Visual / Q000235:genetics; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007930:Leucine / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008564:Membrane Potentials / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D018408:Patch-Clamp Techniques; D020371:Pelizaeus-Merzbacher Disease / Q000175:diagnosis / Q000235:genetics*; D014162:Transfection
chemical_list: D017630:Connexins; C427305:connexin 47; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D001120:Arginine; D007930:Leucine