Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations.

TitleHereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations.
Publication TypeJournal Article
Year of Publication2009
AuthorsOrthmann-Murphy, JL, Salsano, E, Abrams, CK, Bizzi, A, Uziel, G, Freidin, MM, Lamantea, E, Zeviani, M, Scherer, SS, Pareyson, D
JournalBrain
Volume132
IssuePt 2
Pagination426-38
Date Published2009 Feb
ISSN1460-2156
KeywordsAdult, Brain, Connexin 43, Connexins, Evoked Potentials, Female, HeLa Cells, Humans, Magnetic Resonance Imaging, Male, Microscopy, Fluorescence, Middle Aged, Mutation, Patch-Clamp Techniques, Pedigree, Phenotype, Spastic Paraplegia, Hereditary
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.

DOI10.1093/brain/awn328
Alternate JournalBrain
Citation Key10.1093/brain/awn328
PubMed ID19056803
PubMed Central IDPMC2640216
Grant ListK02 NS050345 / NS / NINDS NIH HHS / United States
K02 NS050345-04 / NS / NINDS NIH HHS / United States
K02 NS050345-05 / NS / NINDS NIH HHS / United States
NS050345 / NS / NINDS NIH HHS / United States
NS050705 / NS / NINDS NIH HHS / United States
NS55284 / NS / NINDS NIH HHS / United States
R01 NS050705 / NS / NINDS NIH HHS / United States
R01 NS050705-04 / NS / NINDS NIH HHS / United States
R01 NS050705-05 / NS / NINDS NIH HHS / United States