RGD Reference Report - Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations. - Rat Genome Database

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

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 
Citation: Orthmann-Murphy JL, etal., Brain. 2009 Feb;132(Pt 2):426-38. doi: 10.1093/brain/awn328. Epub 2008 Dec 4.
RGD ID: 13208577
Pubmed: PMID:19056803   (View Abstract at PubMed)
PMCID: PMC2640216   (View Article at PubMed Central)
DOI: DOI:10.1093/brain/awn328   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
GJC2Humanhereditary spastic paraplegia 44  IAGP DNA:missense mutation:cds:p.I33M (human)RGD 
Gjc2Rathereditary spastic paraplegia 44  ISOGJC2 (Homo sapiens)DNA:missense mutation:cds:p.I33M (human)RGD 
Gjc2Mousehereditary spastic paraplegia 44  ISOGJC2 (Homo sapiens)DNA:missense mutation:cds:p.I33M (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Gjc2  (gap junction protein, gamma 2)

Genes (Mus musculus)
Gjc2  (gap junction protein, gamma 2)

Genes (Homo sapiens)
GJC2  (gap junction protein gamma 2)


Additional Information