Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik

Permanent URI for this collectionhttps://hdl.handle.net/11147/9

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Author: search.filters.author.White, Thomas W.WoS Q: search.filters.wosQuartile.Q3

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  • Article
    Citation - WoS: 23
    Citation - Scopus: 24
    Pathological Hemichannels Associated With Human Cx26 Mutations Causing Keratitis-Ichthyosis Syndrome
    (Elsevier Ltd., 2012) Levit, Noah A.; Meşe Özçivici, Gülistan; Meşe, Gülistan; Meşe Özçivici, Gülistan; Basaly, Mena George R.; White, Thomas W.
    Abstract Connexin (Cx) proteins form intercellular gap junction channels by first assembling into single membrane hemichannels that then dock to connect the cytoplasm of two adjacent cells. Gap junctions are highly specialized structures that allow the direct passage of small molecules between cells to maintain tissue homeostasis. Functional activity of nonjunctional hemichannels has now been shown in several experimental systems. Hemichannels may constitute an important diffusional exchange pathway with the extracellular space, but the extent of their normal physiological role is currently unknown. Aberrant hemichannel activity has been linked to mutations of connexin proteins involved in genetic diseases. Here, we review a proposed role for hemichannels in the pathogenesis of Keratitis-Ichthyosis-Deafness (KID) syndrome associated with connexin26 (Cx26) mutations. Continued functional evaluation of mutated hemichannels linked to human hereditary disorders may provide additional insights into the mechanisms governing their regulation in normal physiology and dysregulation in disease. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics. © 2011 Elsevier B.V.
  • Article
    Citation - WoS: 79
    Citation - Scopus: 80
    The Cx26-G45e Mutation Displays Increased Hemichannel Activity in a Mouse Model of the Lethal Form of Keratitis-Ichthyosis Syndrome
    (American Society for Cell Biology, 2011) Meşe, Gülistan; Sellitto, Caterina; Li, Leping; Wang, Hongzhan; Valiunas, Virginijus; Richard, Gabriele; Brink, Peter R.; White, Thomas W.
    Mutations in the GJB2 gene (Cx26) cause deafness in humans. Most are loss-of-function mutations and cause nonsyndromic deafness. Some mutations produce a gain of function and cause syndromic deafness associated with skin disorders, such as keratitis-ichthyosis-deafness syndrome (KIDS). Cx26-G45E is a lethal mutation linked to KIDS that forms constitutively active connexin hemichannels. The pathomechanism(s) by which mutant Cx26 hemichannels perturb normal epidermal cornification are poorly understood. We created an animal model for KIDS by generating an inducible transgenic mouse expressing Cx26-G45E in keratinocytes. Cx26-G45E mice displayed reduced viability, hyperkeratosis, scaling, skin folds, and hair loss. Histopathology included hyperplasia, acanthosis, papillomatosis, increased cell size, and osteal plugging. These abnormalities correlated with human KIDS pathology and were associated with increased hemichannel currents in transgenic keratinocytes. These results confirm the pathogenic nature of the G45E mutation and provide a new model for studying the role of aberrant connexin hemichannels in epidermal differentiation and inherited connexin disorders.