Gap junctions in inherited human disorders of the central nervous system

Abstract

CNS glia and neurons express connexins, the proteins that form gap junctions in vertebrates. We review the connexins expressed by oligodendrocytes and astrocytes, and discuss their proposed physiologic roles. Of the 21 members of the human connexin family, mutations in three are associated with significant central nervous system manifestations. For each, we review the phenotype and discuss possible mechanisms of disease. Mutations in GJB1, the gene for connexin 32 (Cx32) cause the second most common form of Charcot-Marie-Tooth disease (CMT1X). Though the only consistent phenotype in CMT1X patients is a peripheral demyelinating neuropathy, CNS signs and symptoms have been found in some patients with CMT1X. Recessive mutations in GJC2, the gene for Cx47, are one cause of Pelizaeus-Merzbacher-like disease (PMLD), which is characterized by nystagmus within the first 6 months of life, cerebellar ataxia by 4 years, and spasticity by 6 years of age. MRI imaging shows abnormal myelination. A different recessive GJC2 mutation causes a form of hereditary spastic paraparesis, which is a milder phenotype than PMLD. Dominant mutations in GJA1, the gene for Cx43, cause oculodentodigital dysplasia (ODDD), a pleitropic disorder characterized by oculo-facial abnormalities including micropthalmia, microcornia and hypoplastic nares, syndactyly of the fourth to fifth fingers and dental abnormalities. Neurologic manifestations, including spasticity and gait difficulties, are often but not universally seen. Recessive GJA1 mutations cause Hallermann-Streiff syndrome, a disorder showing substantial overlap with ODDD.

A Review of X-linked Charcot-Marie-Tooth Disease

“…21,22 They also have a role in the regulation of cell growth and resistance to cell death. 23 Prior to the first report by Bergoffen et al 8 in 1993 showing 7 different GJB1 mutations in people from 8 CMTX families using direct sequencing, Gal et al 24 suggested that the gene responsible for CMTX1 is located on the proximal long arm of the X chromosome in 1985, and Kumar and Gilula 10 isolated the human CX32 gene from a human liver cDNA library in 1986. To date, more than 400 mutations in GJB1 have been described 9 and are thought to affect all regions of the connexin 32 protein.…”

A new mutation in GJC2 associated with subclinical leukodystrophy

“…Many connexins family can form functional GJs by associating with a like connexon (a homotypic junction) or a different one (a heterotypic junction). At least six connexins have been identified in CNS glia - Cx26, Cx30, and Cx43 in astrocytes, and Cx29/Cx30.3, Cx32, and Cx47 in oligodendrocytes [3]. Astrocytes can form homologous GJs (A/A GJs) comprised of Cx30:Cx30, Cx43:Cx43, and perhaps Cx26:Cx26 homotypic channels, oligodendrocytes can form homologous GJs (O/O GJs) comprised of Cx32:Cx32 and Cx47:Cx47 homotypic channels [23, 44], and oligodendrocytes can form GJs with astrocytes (O/A GJs) comprised of Cx32:Cx30 and Cx47:Cx43 [30] and perhaps Cx47:Cx30 heterotypic channels [23].…”

Oligodendrocytes: Myelination and Axonal Support

“…In the adult nervous system, they may provide a functional connection between the oligodendroglial soma and the periaxonal space, allowing the distribution of glial metabolites to the axonal compartment. Considering that oligodendrocytes are also interconnected through gap junctions with each other and astrocytes, glial cells may provide a functional "syncytium" within white matter tracts (Abrams and Scherer 2012;Bedner et al 2012;NualartMarti et al 2013). …”