Journal Article

Hereditary spastic paraplegia is a novel phenotype for <i>GJA12/GJC2</i> mutations

Jennifer L. Orthmann-Murphy, Ettore Salsano, Charles K. Abrams, Alberto Bizzi, Graziella Uziel, Mona M. Freidin, Eleonora Lamantea, Massimo Zeviani, Steven S. Scherer and Davide Pareyson

in Brain

Published on behalf of The Guarantors of Brain

Volume 132, issue 2, pages 426-438
Published in print February 2009 | ISSN: 0006-8950
Published online December 2008 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awn328
Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations

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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.

Keywords: spastic paraplegias; Pelizaeus-Merzbacher-like disease; gap junction; connexin; oligodendrocyte

Journal Article.  7825 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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