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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)426-438
Number of pages13
JournalBrain
Volume132
Issue number2
DOIs
Publication statusPublished - Feb 2009

Keywords

  • Connexin
  • Gap junction
  • Oligodendrocyte
  • Pelizaeus-Merzbacher-like disease
  • Spastic paraplegias

ASJC Scopus subject areas

  • Clinical Neurology

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