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Mechanisms linking connexin mutations to human diseases

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Abstract

Ubiquitously expressed connexins are tetra-spanning transmembrane proteins that form intercellular gap junction channels or cell surface hemichannels. Connexins share similar topology but no sequence homology with mammalian pannexins and CALHM1 (calcium homeostasis modulator 1), which are also large-pore transmembrane channels. Of these three channel types, clinical evidence and gene sequence analysis to date have revealed that inherited human diseases are only associated with mutations in the connexin gene family. Connexin-linked diseases often present at birth or early in life and range from mild developmental abnormalities to severe organ failure such as hearing loss. Inherited connexin gene mutations can manifest as a disease by causing anomalies or defects in connexin oligomerization, folding, ability to pass quality control mechanisms or unexpected gain- or loss-of-function. This review provides examples of the way that various connexin gene mutations can cause disease via a wide range of molecular mechanisms. We also reflect on exciting strategies being explored in the connexin field and beyond with a view of translating their findings into potential connexin-disease therapeutics.

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Acknowledgments

The authors apologize for the vast number of studies that are not cited in this review as this field is large and only examples of key findings are reported here. We also thank Dr. Silvia Penuela for helpful discussions.

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, N6A-5C1, Canada

    John J. Kelly & Jamie Simek

  2. Canada Research Chair in Gap Junctions and Disease, Department of Anatomy and Cell Biology, University of Western Ontario, Dental Science Building, Rm 00077, London, ON, Canada, N6A-5C1

    Dale W. Laird

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  1. John J. Kelly
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  2. Jamie Simek
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  3. Dale W. Laird
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Corresponding author

Correspondence to Dale W. Laird.

Additional information

This work was supported by the Canadian Institutes of Health Research (74637, 123338) to D.W.L.

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Kelly, J.J., Simek, J. & Laird, D.W. Mechanisms linking connexin mutations to human diseases. Cell Tissue Res 360, 701–721 (2015). https://doi.org/10.1007/s00441-014-2024-4

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