Brain Advance Access first published online on December 4, 2008
This version published online on January 20, 2009
Brain, doi:10.1093/brain/awn328
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Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations
1 Department of Neurology, University of Pennsylvania School of Medicine, Room 464 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104-6077, USA, 2 Biochemistry and Genetics Unit, IRCCS Foundation, C. Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy, 3 Department of Neurology, 4 Department of Physiology and Pharmacology, SUNY Downstate Medical Center, Box 1213, 450 Clarkson Avenue, Brooklyn, NY 11203, USA, 5 Neuroradiology Unit, 6 Child Neurology Unit and 7 Molecular Neurogenetics Unit, IRCCS Foundation, C. Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy
Correspondence to:
Davide Pareyson, MD, Biochemistry and Genetics Unit, IRCCS Foundation, C. Besta Neurological Institute, Via Celoria 11, 20133 Milan, Italy E-mail: dpareys{at}istituto-besta.it
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.
Key Words: spastic paraplegias; Pelizaeus-Merzbacher-like disease; gap junction; connexin; oligodendrocyte
Abbreviations: Cx47, connexin47; DTRs, deep tendon reflexes; ER, endoplasmic reticulum; HSP, hereditary spastic paraplegia; PMD, Pelizaeus-Merzbacher disease; PMLD, Pelizaeus-Merzbacher-like disease
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Received September 16, 2008. Revised October 27, 2008. Accepted November 4, 2008.
After this paper was published online, SPG44 (not SPG42) was assigned as an alias to GJC2 (see http://www.genenames.org)