Neurological manifestations of oculodentodigital dysplasia: a Cx43 channelopathy of the central nervous system?

Abstract

The coordination of tissue function is mediated by gap junctions (GJs) that enable direct cell–cell transfer of metabolic and electric signals. GJs are formed by connexins of which Cx43 is most widespread in the human body. In the brain, Cx43 GJs are mostly found in astroglia where they coordinate the propagation of Ca2+ waves, spatial K+ buffering, and distribution of glucose. Beyond its role in direct intercellular communication, Cx43 also forms unapposed, non-junctional hemichannels in the plasma membrane of glial cells. These allow the passage of several neuro- and gliotransmitters that may, combined with downstream paracrine signaling, complement direct GJ communication among glial cells and sustain glial-neuronal signaling. Mutations in the GJA1 gene encoding Cx43 have been identified in a rare, mostly autosomal dominant syndrome called oculodentodigital dysplasia (ODDD). ODDD patients display a pleiotropic phenotype reflected by eye, hand, teeth, and foot abnormalities, as well as craniofacial and bone malformations. Remarkably, neurological symptoms such as dysarthria, neurogenic bladder (manifested as urinary incontinence), spasticity or muscle weakness, ataxia, and epilepsy are other prominent features observed in ODDD patients. Over 10 mutations detected in patients diagnosed with neurological disorders are associated with altered functionality of Cx43 GJs/hemichannels, but the link between ODDD-related abnormal channel activities and neurologic phenotype is still elusive. Here, we present an overview on the nature of the mutants conveying structural and functional changes of Cx43 channels and discuss available evidence for aberrant Cx43 GJ and hemichannel function. In a final step, we examine the possibilities of how channel dysfunction may lead to some of the neurological manifestations of ODDD.

Mouse Hepatitis Virus Infection Remodels Connexin43-Mediated Gap Junction Intercellular Communication In Vitro and In Vivo

“…Previous studies have shown that the deletion of astrocytes Cx43 and Cx30 (10) or oligodendrocytes Cx47 and Cx32 (58) can cause pathological conditions featuring demyelination and oligodendrocyte cell death. In a human channelopathy, ODDD, Cx43 mutation can cause the loss of visual function and demyelination, which is similar to effects of MS (59). Furthermore, Cx43/Cx47 is reported to be critical for human myelination under disease conditions (60,61).…”

Junctional proteins of the blood-brain barrier: New insights into function and dysfunction

“…94 Germline mutations in the N-terminal region of Cx43 are known to cause oculodentodigital dysplasia (ODDD) in humans, a disease characterized by varying degrees of physical deformity in eyes, teeth and limbs. 95 Approximately 30% of ODDD patients develop neuropathies. While it's generally accepted that these neuropathies arise from astrocyte-specific Cx43 defects in neuron-coupling, it has not been described whether the BBB is affected and contributes.…”

Genetic defects disrupting glial ion and water homeostasis in the brain

“…ODDD is characterized by abnormalities of the eyes, teeth and fingers, underlining the importance of gap junctions in other tissues. Neurological signs are typically relatively mild and include ataxia, epilepsy and loss of vision and hearing .…”