Connexin 26 (GJB2) mutations, causing KID Syndrome, are associated with cell death due to calcium gating deregulation

Terrinoni, Alessandro; Codispoti, Andrea; Serra, Valeria; Didona, Biagio; Bruno, Ernesto; Nisticò, Robert; Giustizieri, Michela; Alessandrini, Marco; Campione, Elena; Melino, Gerry

doi:10.1016/j.bbrc.2010.03.073

Cited by 37 publications

(41 citation statements)

References 46 publications

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“…It has been previously demonstrated that other dominant Cx26 mutations associated with KID syndrome produced abnormal hemichannel currents in cells, leading to accelerated death (13,21,31,41,42). Previous studies have also shown that increased extracellular calcium reduced hemichannel activity and delayed cell death (11,13,21,32,37,41).…”

Section: Resultsmentioning

confidence: 94%

The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity

Mhaske

Levit

et al. 2013

American Journal of Physiology-Cell Physiology

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Mutations in the human gene encoding connexin 26 (Cx26 or GJB2) cause either nonsyndromic deafness or syndromic deafness associated with skin diseases. That distinct clinical disorders can be caused by different mutations within the same gene suggests that different channel activities influence the ear and skin. Here we use three different expression systems to examine the functional characteristics of two Cx26 mutations causing either mild (Cx26-D50A) or lethal (Cx26-A88V) keratitis-ichthyosis-deafness (KID) syndrome. In either cRNA-injected Xenopus oocytes, transfected HeLa cells, or transfected primary human keratinocytes, we show that both Cx26-D50A and Cx26-A88V form active hemichannels that significantly increase membrane current flow compared with wild-type Cx26. This increased membrane current accelerated cell death in low extracellular calcium solutions and was not due to increased mutant protein expression. Elevated mutant hemichannel currents could be blocked by increased extracellular calcium concentration. These results show that these two mutations exhibit a shared gain of functional activity and support the hypothesis that increased hemichannel activity is a common feature of human Cx26 mutations responsible for KID syndrome.

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Section: Resultsmentioning

confidence: 94%

The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity

Mhaske

Levit

et al. 2013

American Journal of Physiology-Cell Physiology

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“…The vast majority of Cx26 mutations linked to KIDS have been shown to display increased hemichannel activity (Montgomery et al , 2004; Stong et al , 2006; Gerido et al , 2007; Lee et al , 2009; Sanchez et al , 2010; Terrinoni et al , 2010). Biophysical studies of Cx26-A40V and Cx26-G45E hemichannels found that both showed impaired regulation by extracellular Ca 2+ , increasing the likelihood of aberrant hemichannel opening.…”

Section: Discussionmentioning

confidence: 99%

“…At least 10 different Cx26 mutations have been linked to KIDS in humans, and in vitro analysis demonstrated that the majority of these mutations lead to constitutively active hemichannels that significantly compromise cell viability and intracellular calcium homeostasis (Montgomery et al , 2004; Stong et al , 2006; Gerido et al , 2007; Lee et al , 2009; Sanchez et al , 2010; Terrinoni et al , 2010). Although the in vitro evidence generated thus far strongly suggests that hemichannel dysfunction significantly compromises cell homeostasis, the role of mutant Cx26 hemichannels in vivo during epidermal differentiation is still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome

Meşe

Sellitto

et al. 2011

MBoC

103

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“…The cochlear gap-junctional communication network includes several different cell types and is essential for hearing (Steel, 1999; Forge and Wright, 2002; Forge et al, 2003; Wangemann, 2006; Nickel and Forge, 2008). Profound hearing loss of genetic origin is common (~1 in 2000 children) and mutations of Cx26, the main connexin in the inner ear, are its major cause (Steel, 2000; Ravecca et al, 2005; Sabag et al, 2005; Apps et al, 2007; Nickel and Forge, 2008; Lee and White, 2009; Martinez et al, 2009; Laird, 2010; Terrinoni et al, 2010; Zoidl and Dermietzel, 2010). …”

Section: Connexin 26mentioning

confidence: 99%

Functional analysis and regulation of purified connexin hemichannels

et al. 2014

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Gap-junction channels (GJCs) are aqueous channels that communicate adjacent cells. They are formed by head-to-head association of two hemichannels (HCs), one from each of the adjacent cells. Functional HCs are connexin hexamers composed of one or more connexin isoforms. Deafness is the most frequent sensineural disorder, and mutations of Cx26 are the most common cause of genetic deafness. Cx43 is the most ubiquitous connexin, expressed in many organs, tissues, and cell types, including heart, brain, and kidney. Alterations in its expression and function play important roles in the pathophysiology of very frequent medical problems such as those related to cardiac and brain ischemia. There is extensive information on the relationship between phosphorylation and Cx43 targeting, location, and function from experiments in cells and organs in normal and pathological conditions. However, the molecular mechanisms of Cx43 regulation by phosphorylation are hard to tackle in complex systems. Here, we present the use of purified HCs as a model for functional and structural studies. Cx26 and Cx43 are the only isoforms that have been purified, reconstituted, and subjected to functional and structural analysis. Purified Cx26 and Cx43 HCs have properties compatible with those demonstrated in cells, and present methodologies for the functional analysis of purified HCs reconstituted in liposomes. We show that phosphorylation of serine 368 by PKC produces a partial closure of the Cx43 HCs, changing solute selectivity. We also present evidence that the effect of phosphorylation is highly cooperative, requiring modification of several connexin subunits, and that phosphorylation of serine 368 elicits conformational changes in the purified HCs. The use of purified HCs is starting to provide critical data to understand the regulation of HCs at the molecular level.

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Connexin 26 (GJB2) mutations, causing KID Syndrome, are associated with cell death due to calcium gating deregulation

Cited by 37 publications

References 46 publications

The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity

The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity

The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome

Functional analysis and regulation of purified connexin hemichannels

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