Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Pelizaeus-Merzbacher-like disease is caused not only by a loss of connexin47 function but also by a hemichannel dysfunction.
Diekmann S
,
Henneke M
,
Burckhardt BC
,
Gärtner J
.
???displayArticle.abstract???
Autosomal recessive mutations in the GJA12/GJC2 gene encoding the gap junction protein connexin47 (C x 47) cause a form of Pelizaeus-Merzbacher-like disease (PMLD) with hypomyelination, nystagmus, impaired psychomotor development and progressive spasticity. We investigated the functional consequences of four C x 47 missense mutations (G149S, G236R, T265A, and T398I) and one C x 47 complex mutation (A98G_V99insT) by immunoblot analysis and immunocytochemistry in transfected communication-incompetent HeLa cells and in OLI-neu cells. All studied C x 47 mutants, except G236R, generated stable proteins in transfected HeLa cells and OLI-neu cells. The mutants T265A and A98G_V99insT were retained in the ER, T398I formed gap junctional plaques at the plasma membrane, and G149S showed both, structures at the plasma membrane and ER localization. Two-microelectrode voltage clamp analyses in Xenopus laevis oocytes injected with wild-type and mutant C x 47 cRNA revealed reduced hemichannel currents for G236R, T265A, and A98G_V99insT. In contrast, T398I revealed hemichannel currents comparable to wild-type. For C x 47 mutant T398I, our results indicate a defect in hemichannel function, whereas C x 47 mutants G149S, G236R, T265A, and A98G_V99insT are predicted to result in a loss of C x 47 hemichannel function. Thus, PMLD is likely to be caused by two different disease mechanisms: a loss of function and a dysfunction.
Aridor,
Integration of endoplasmic reticulum signaling in health and disease.
1999, Pubmed
Aridor,
Integration of endoplasmic reticulum signaling in health and disease.
1999,
Pubmed
Barish,
A transient calcium-dependent chloride current in the immature Xenopus oocyte.
1983,
Pubmed
,
Xenbase
Barrio,
Gap junctions formed by connexins 26 and 32 alone and in combination are differently affected by applied voltage.
1991,
Pubmed
,
Xenbase
Britz-Cunningham,
Mutations of the Connexin43 gap-junction gene in patients with heart malformations and defects of laterality.
1995,
Pubmed
Bugiani,
GJA12 mutations in children with recessive hypomyelinating leukoencephalopathy.
2006,
Pubmed
Castro,
Altered formation of hemichannels and gap junction channels caused by C-terminal connexin-32 mutations.
1999,
Pubmed
,
Xenbase
D'Urso,
Overloaded endoplasmic reticulum-Golgi compartments, a possible pathomechanism of peripheral neuropathies caused by mutations of the peripheral myelin protein PMP22.
1998,
Pubmed
Deschênes,
Altered trafficking of mutant connexin32.
1997,
Pubmed
Dhaunchak,
A common mechanism of PLP/DM20 misfolding causes cysteine-mediated endoplasmic reticulum retention in oligodendrocytes and Pelizaeus-Merzbacher disease.
2007,
Pubmed
Ebihara,
New roles for connexons.
2003,
Pubmed
Foote,
The pattern of disulfide linkages in the extracellular loop regions of connexin 32 suggests a model for the docking interface of gap junctions.
1998,
Pubmed
,
Xenbase
Giaume,
Gap junctions in cultured astrocytes: single-channel currents and characterization of channel-forming protein.
1991,
Pubmed
Gow,
Many naturally occurring mutations of myelin proteolipid protein impair its intracellular transport.
1994,
Pubmed
Gow,
A cellular mechanism governing the severity of Pelizaeus-Merzbacher disease.
1996,
Pubmed
Gow,
Disrupted proteolipid protein trafficking results in oligodendrocyte apoptosis in an animal model of Pelizaeus-Merzbacher disease.
1998,
Pubmed
Henneke,
GJA12 mutations are a rare cause of Pelizaeus-Merzbacher-like disease.
2008,
Pubmed
Jung,
Lines of murine oligodendroglial precursor cells immortalized by an activated neu tyrosine kinase show distinct degrees of interaction with axons in vitro and in vivo.
1995,
Pubmed
Kondo,
Metabolic inhibition activates a non-selective current through connexin hemichannels in isolated ventricular myocytes.
2000,
Pubmed
Kozak,
Interpreting cDNA sequences: some insights from studies on translation.
1996,
Pubmed
Kumar,
The gap junction communication channel.
1996,
Pubmed
Liang,
Severe neuropathy with leaky connexin32 hemichannels.
2005,
Pubmed
,
Xenbase
Massa,
Cell junctions and intramembrane particles of astrocytes and oligodendrocytes: a freeze-fracture study.
1982,
Pubmed
Menichella,
Connexins are critical for normal myelination in the CNS.
2003,
Pubmed
Moreno,
Gap junction channel gating modulated through protein phosphorylation.
2007,
Pubmed
Nagy,
Evidence for the co-localization of another connexin with connexin-43 at astrocytic gap junctions in rat brain.
1997,
Pubmed
Nagy,
Connexin26 in adult rodent central nervous system: demonstration at astrocytic gap junctions and colocalization with connexin30 and connexin43.
2001,
Pubmed
Nagy,
Update on connexins and gap junctions in neurons and glia in the mammalian nervous system.
2004,
Pubmed
Odermatt,
Connexin 47 (Cx47)-deficient mice with enhanced green fluorescent protein reporter gene reveal predominant oligodendrocytic expression of Cx47 and display vacuolized myelin in the CNS.
2003,
Pubmed
Olbina,
Mutations in the second extracellular region of connexin 43 prevent localization to the plasma membrane, but do not affect its ability to suppress cell growth.
2003,
Pubmed
Omori,
Connexin 32 mutations from X-linked Charcot-Marie-Tooth disease patients: functional defects and dominant negative effects.
1996,
Pubmed
Orthmann-Murphy,
Gap junctions couple astrocytes and oligodendrocytes.
2008,
Pubmed
Orthmann-Murphy,
Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations.
2009,
Pubmed
Orthmann-Murphy,
Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus-Merzbacher-like disease.
2007,
Pubmed
Orthmann-Murphy,
Two distinct heterotypic channels mediate gap junction coupling between astrocyte and oligodendrocyte connexins.
2007,
Pubmed
Rash,
Cell-specific expression of connexins and evidence of restricted gap junctional coupling between glial cells and between neurons.
2001,
Pubmed
Salviati,
A novel deletion in the GJA12 gene causes Pelizaeus-Merzbacher-like disease.
2007,
Pubmed
Saugier-Veber,
X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus.
1994,
Pubmed
Schiffmann,
An update on the leukodsytrophies.
2001,
Pubmed
Trosko,
Cell-cell communication in carcinogenesis.
1998,
Pubmed
Uhlenberg,
Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.
2004,
Pubmed
Wang,
Two novel gap junction protein alpha 12 gene mutations in two Chinese patients with Pelizaeus-Merzbacher-like disease.
2010,
Pubmed
Wolf,
Frameshift mutation in GJA12 leading to nystagmus, spastic ataxia and CNS dys-/demyelination.
2007,
Pubmed