Connexin26 hemichannels with a mutation that causes KID syndrome in humans lack sensitivity to CO2

Abstract Mutations in connexin26 (Cx26) underlie a range of serious human pathologies. Previously we have shown that Cx26 hemichannels are directly opened by CO2 (Meigh et al., 2013). However the effects of human disease-causing mutations on the CO2 sensitivity of Cx26 are entirely unknown. Here, we report the first connection between the CO2 sensitivity of Cx26 and human pathology, by demonstrating that Cx26 hemichannels with the mutation A88V, linked to Keratitis-Ichthyosis-Deafness syndrome, are both CO2 insensitive and associated with disordered breathing in humans. DOI: http://dx.doi.org/10.7554/eLife.04249.001

[1]  K. Willecke,et al.  The Clouston syndrome mutation connexin30 A88V leads to hyperproliferation of sebaceous glands and hearing impairments in mice , 2014, FEBS letters.

[2]  V. Cruciani,et al.  The vertebrate connexin family , 2006, Cellular and Molecular Life Sciences CMLS.

[3]  D. Paul,et al.  Connexins: functions without junctions. , 2004, Current opinion in cell biology.

[4]  C. Bodemer,et al.  A familial case of Keratitis-Ichthyosis-Deafness (KID) syndrome with the GJB2 mutation G45E. , 2008, European journal of medical genetics.

[5]  N. Dale,et al.  CO2 directly modulates connexin 26 by formation of carbamate bridges between subunits , 2013, eLife.

[6]  Robert T. R. Huckstepp,et al.  CO2‐dependent opening of connexin 26 and related β connexins , 2010, The Journal of physiology.

[7]  A. Charollais,et al.  Connexin30 mutations responsible for hidrotic ectodermal dysplasia cause abnormal hemichannel activity. , 2004, Human molecular genetics.

[8]  W. Kimberling,et al.  Connexin 26: required for normal auditory function , 2000, Brain Research Reviews.

[9]  C. Bodemer,et al.  Germline mosaicism in keratitis–ichthyosis–deafness syndrome: pre‐natal diagnosis in a familial lethal form , 2010, Clinical genetics.

[10]  A. Takakura,et al.  Regulation of ventral surface CO2/H+‐sensitive neurons by purinergic signalling , 2012, The Journal of physiology.

[11]  D Curran-Everett,et al.  Multiple comparisons: philosophies and illustrations. , 2000, American journal of physiology. Regulatory, integrative and comparative physiology.

[12]  C. Durán-McKinster,et al.  Keratitis, Ichthyosis, and Deafness (KID Syndrome): Review of the Literature and Proposal of a New Terminology , 2010, Pediatric dermatology.

[13]  Robert T. R. Huckstepp,et al.  Connexin hemichannel‐mediated CO2‐dependent release of ATP in the medulla oblongata contributes to central respiratory chemosensitivity , 2010, The Journal of physiology.

[14]  T. W. White,et al.  The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity. , 2013, American journal of physiology. Cell physiology.

[15]  U. Koppelhus,et al.  A novel mutation in the connexin 26 gene (GJB2) in a child with clinical and histological features of keratitis–ichthyosis–deafness (KID) syndrome , 2011, Clinical and experimental dermatology.

[16]  H. Hennies,et al.  GJB2 mutations in keratitis‐ichthyosis‐deafness syndrome including its fatal form , 2005, American journal of medical genetics. Part A.

[17]  G. Richard,et al.  Aberrant hemichannel properties of Cx26 mutations causing skin disease and deafness. , 2007, American journal of physiology. Cell physiology.

[18]  P. M. Kelley,et al.  Clinical phenotype and mutations in connexin 26 (DFNB1/GJB2), the most common cause of childhood hearing loss. , 1999, American journal of medical genetics.

[19]  Ji Xu,et al.  The role of connexins in ear and skin physiology - functional insights from disease-associated mutations. , 2013, Biochimica et biophysica acta.

[20]  Toshiaki Shimizu,et al.  Severe form of keratitis–ichthyosis–deafness (KID) syndrome associated with septic complications , 2010, The Journal of dermatology.

[21]  Thomas W. White,et al.  Differentially altered Ca2+ regulation and Ca2+ permeability in Cx26 hemichannels formed by the A40V and G45E mutations that cause keratitis ichthyosis deafness syndrome , 2010, The Journal of general physiology.

[22]  V. Rogiers,et al.  Paracrine signaling through plasma membrane hemichannels. , 2013, Biochimica et biophysica acta.

[23]  HighWire Press,et al.  American journal of physiology. Cell physiology , 1977 .