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 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.
Orthmann-Murphy
Jennifer L
JL
Department of Neurology, University of Pennsylvania School of Medicine, Room 464 Stemmler Hall, Philadelphia, PA 19104-6077, USA.
Salsano
Ettore
E
Abrams
Charles K
CK
Bizzi
Alberto
A
Uziel
Graziella
G
Freidin
Mona M
MM
Lamantea
Eleonora
E
Zeviani
Massimo
M
Scherer
Steven S
SS
Pareyson
Davide
D
D000328:Adult; D001921:Brain / Q000473:pathology; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D005071:Evoked Potentials; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009154:Mutation; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D018031:Connexin 43; D017630:Connexins; C427305:connexin 47