title: Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations.
abstract: Recessive mutations in GJA12/GJC2, the gene that encodes the gap junction protein connexin47 (Cx47), cause Pelizaeus-Merzbacher-like disease (PMLD), an early onset dysmyelinating disorder of the CNS, characterized by nystagmus, psychomotor delay, progressive spasticity and cerebellar signs. Here we describe three patients from one family with a novel recessively inherited mutation, 99C>G (predicted to cause an Ile>Met amino acid substitution; I33M) that causes a milder phenotype. All three had a late-onset, slowly progressive, complicated spastic paraplegia, with normal or near-normal psychomotor development, preserved walking capability through adulthood, and no nystagmus. MRI and MR spectroscopy imaging were consistent with a hypomyelinating leukoencephalopathy. The mutant protein forms gap junction plaques at cell borders similar to wild-type (WT) Cx47 in transfected cells, but fails to form functional homotypic channels in scrape-loading and dual whole-cell patch clamp assays. I33M forms overlapping gap junction plaques and functional channels with Cx43, however, I33M/Cx43 channels open only when a large voltage difference is applied to paired cells. These channels probably do not function under physiological conditions, suggesting that Cx47/Cx43 channels between astrocytes and oligodendrocytes are disrupted, similar to the loss-of-function endoplasmic reticulum-retained Cx47 mutants that cause PMLD. Thus, GJA12/GJC2 mutations can result in a milder phenotype than previously appreciated, but whether I33M retains a function of Cx47 not directly related to forming functional gap junction channels is not known.
authors.affiliation: Department of Neurology, University of Pennsylvania School of Medicine, Room 464 Stemmler Hall, Philadelphia, PA 19104-6077, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Orthmann-Murphy
authors.forename: Ettore
authors.initials: E
authors.lastname: Salsano
authors.forename: Charles K
authors.initials: CK
authors.lastname: Abrams
authors.forename: Alberto
authors.initials: A
authors.lastname: Bizzi
authors.forename: Graziella
authors.initials: G
authors.lastname: Uziel
authors.forename: Mona M
authors.initials: MM
authors.lastname: Freidin
authors.forename: Eleonora
authors.initials: E
authors.lastname: Lamantea
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.forename: Steven S
authors.initials: SS
authors.lastname: Scherer
authors.forename: Davide
authors.initials: D
authors.lastname: Pareyson
mesh_terms: D000328:Adult; D001921:Brain / Q000473:pathology; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D005071:Evoked Potentials; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009154:Mutation; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D018031:Connexin 43; D017630:Connexins; C427305:connexin 47