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

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...

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Bibliographic Details
Published in:	Brain (London, England : 1878) England : 1878), 2009-02, Vol.132 (2), p.426-438
Main Authors:	Orthmann-Murphy, Jennifer L., Salsano, Ettore, Abrams, Charles K., Bizzi, Alberto, Uziel, Graziella, Freidin, Mona M., Lamantea, Eleonora, Zeviani, Massimo, Scherer, Steven S., Pareyson, Davide
Format:	Article
Language:	eng
Subjects:	Adult Biological and medical sciences Brain - pathology connexin Connexin 43 - genetics Connexin 43 - metabolism Connexins - genetics Connexins - metabolism Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Evoked Potentials Female gap junction HeLa Cells Humans Magnetic Resonance Imaging Male Medical sciences Microscopy, Fluorescence Middle Aged Mutation Neurology oligodendrocyte Original Patch-Clamp Techniques Pedigree Pelizaeus-Merzbacher-like disease Phenotype Spastic Paraplegia, Hereditary - genetics Spastic Paraplegia, Hereditary - metabolism Spastic Paraplegia, Hereditary - pathology spastic paraplegias
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Summary:	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.
ISSN:	0006-8950 1460-2156