Thomas W. White
Associate Professor
Department of Physiology and Biophysics
T5-147, Basic Science Tower
State University of New York
Stony Brook, NY 11794-8661
phone: (631) 444-9683
fax: (631) 444-3432
Gap junction functions defined by genetic diseases and gene knockouts.
Intercellular channels present in gap junctions allow cells to share small molecules and thus coordinate a wide range of behaviors. In vertebrates, a large family of genes known as connexins (Cx) encodes these gap junctional channels, and mutations in human connexins underlie a variety of diseases, including deafness, skin diseases (keratodermas), demyelinating neuropathies, and lens cataracts. In addition, gene targeting of connexins in mice has provided new insights into connexin function and revealed a variety of unexpected phenotypes.
We are interested in how different members of the connexin family fulfill unique functions in tissue homeostasis. For example, the lens expresses three connexins Cx43, Cx46 and Cx50. Mutations in either the human Cx46 or Cx50 genes lead to congenital cataract. Using genetically engineered mice with targeted disruption of these connexins, we have found that connexin diversity is not required for embryonic development of the lens but is essential for normal postnatal growth and function.
Normal embryonic eye development after targeted deletion
of two out of three of the mouse lens connexin genes.
Cataract formation in a postnatal mouse lens
with genetically altered connexin expression.
We also use electrophysiological and dye transfer assays to determine the alterations in channel function that arise from connexin mutations that cause human hereditary disease. Mutations in the human Cx26 gene can cause either hearing loss alone, or deafness associated with skin disease (i.e. Vohwinkel syndrome). Using an in vitro expression system for gap junction channels, we have found that simple loss of Cx26 function can only explain a subset of nonsyndromic deafness causing mutations. Those Cx26 mutations that cause skin disease also frequently show loss of Cx26 function, but have additional effects on the activity of other epidermal connexins.
Paired Xenopus oocytes or transiently transfected mammalian cells
are used to assay the activity of wildtype and mutant connexins.
A Cx26 mutation that causes hearing loss and skin disease (DE42)
also inhibits the activity of wildtype Cx43 when co-expressed.
Some mutations that cause hearing loss alone show loss of
function (W77R), while others (V84L) retain channel activity.
Selected Recent Publications
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G. Kanaporis, G. Meşe, L. Valiuniene, T.W. White, P.R. Brink and V. Valiunas (2008). Gap junction channels exhibit connexin-specific permeability to cyclic nucleotides. J. Gen. Physiol. 131:293-305 (pdf) |
T.W. White, Y. Gao, L. Li, C. Sellitto, and M. Srinivas (2007). Changes in lens epithelial cell proliferation are correlated with changes in gap junctional coupling. Invest. Ophthalmol. Vis. Sci. 48:5630-5637 (pdf)
D.A. Gerido, A.M. DeRosa, G. Richard and T.W. White (2007). Aberrant hemichannel properties of Cx26 mutations causing skin disease and deafness. Am. J. Physiol. Cell Physiol. 293:C337-C345 (pdf)
A.M. DeRosa, R. Mui, M. Srinivas and T.W. White (2006) Functional characterization of a naturally occurring Cx50 truncation. Invest. Ophthalmol. Vis. Sci. 47:4474-4481 (pdf)
T.W. White, H. Wang, R. Mui, J. Litteral and P.R. Brink. (2004) Cloning and functional expression of invertebrate connexins from Halocynthia pyriformis. FEBS Letters 577:42-48 (pdf)
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J. Gao, X. Sun, F. Martinez-Wittinghan, X. Gong, T.W. White and R.T. Mathias. (2004) Connections between connexins, calciumand cataracts in the lens. J. Gen. Physiol. 124:289-300 (pdf) |
G. Meşe, E. Londin, R. Mui, P.R. Brink and T.W. White. (2004) Altered gating properties of functional Cx26 mutants associated with recessive non-syndromic hearing loss. Hum. Genet. 115:191-199 (pdf)
C. Sellitto, L. Li, and T.W. White. (2004) Connexin50 is required for normal postnatal lens cell proliferation. Invest. Ophthalmol. Vis. Sci. 45:3196-3202 (pdf)
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F.J. Martinez-Whittinghan, C. Sellitto, L. Li, X. Gong, P.R. Brink, R.T. Mathias and T.W. White. (2003) Dominant cataracts result from incongruous mixing of wild-type lens connexins. J. Cell Biol. 161:969-978 (pdf) |
R. Bruzzone, V. Veronesi, D. Gomes, M. Bicego, N. Duval, S. Marlin, C. Petit, P. D’Andrea and T.W. White. (2003) Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness. FEBS Letters 533:79-88 (pdf)
T.W.
White.
(2002) Unique
and redundant connexin contributions to lens development. Science
295:319-320
