HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 18, 19157-19168, April 30, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/18/19157    most recent M314117200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thomas, T. Articles by Laird, D. W. Search for Related Content PubMed PubMed Citation Articles by Thomas, T. Articles by Laird, D. W. Social Bookmarking                      What's this?

Functional Domain Mapping and Selective Trans-dominant Effects Exhibited by Cx26 Disease-causing Mutations^*

Tamsin Thomas, Debra Telford, and Dale W. Laird

From the Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 5C1, Canada

Mutations in Cx26 are a major cause of autosomal dominant and recessive forms of sensorineural deafness. Some mutations in Cx26 are associated not only with deafness but also with skin disease. We examined the subcellular localization and function of two green fluorescent protein (GFP)-tagged Cx26 point mutants that exhibit both phenotypes, G59A-GFP and D66H-GFP. D66H-GFP was retained within the brefeldin A-insensitive trans-Golgi network, whereas a population of G59A-GFP was transported to the cell surface. Neither G59A nor D66H formed gap junctions that were permeable to small fluorescent dyes, suggesting they are loss-of-function mutations. When co-expressed with wild-type Cx26, both G59A and D66H exerted dominant-negative effects on Cx26 function. G59A also exerted a trans-dominant negative effect on co-expressed wild type Cx32 and Cx43, whereas D66H exerted a trans-dominant negative effect on Cx43 but not Cx32. We propose that the severity of the skin disease is dependent on the specific nature of the Cx26 mutation and the trans-dominant selectivity of the Cx26 mutants on co-expressed connexins. Additional systematic mutations at residue D66, in which the overall charge of this motif was altered, suggested that the first extracellular loop is critical for Cx26 transport to the cell surface as well as function of the resulting gap junction channels.

Received for publication, December 23, 2003

^* This work was supported by a grant from the Canadian Institutes of Health Research (to D. W. L.) and a studentship from the Natural Sciences and Engineering Research Council of Canada (to T. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dental Science Building, Rm 00077, London, Ontario N6A 5C1, Canada. Tel.: 519-661-2111 (ext. 86827); Fax: 519-850-2562; E-mail: dwlaird{at}uwo.ca.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. K. VanSlyke, C. C. Naus, and L. S. Musil Conformational Maturation and Post-ER Multisubunit Assembly of Gap Junction Proteins Mol. Biol. Cell, May 1, 2009; 20(9): 2451 - 2463. [Abstract] [Full Text] [PDF]

				I. Sargiannidou, N. Vavlitou, S. Aristodemou, A. Hadjisavvas, K. Kyriacou, S. S. Scherer, and K. A. Kleopa Connexin32 Mutations Cause Loss of Function in Schwann Cells and Oligodendrocytes Leading to PNS and CNS Myelination Defects J. Neurosci., April 15, 2009; 29(15): 4736 - 4749. [Abstract] [Full Text] [PDF]

				E. A. Banks, M. M. Toloue, Q. Shi, Z. J. Zhou, J. Liu, B. J. Nicholson, and J. X. Jiang Connexin mutation that causes dominant congenital cataracts inhibits gap junctions, but not hemichannels, in a dominant negative manner J. Cell Sci., February 1, 2009; 122(3): 378 - 388. [Abstract] [Full Text] [PDF]

				D. W. Laird Closing the Gap on Autosomal Dominant Connexin-26 and Connexin-43 Mutants Linked to Human Disease J. Biol. Chem., February 8, 2008; 283(6): 2997 - 3001. [Abstract] [Full Text] [PDF]

				C. M. L. Hutnik, C. E. Pocrnich, H. Liu, D. W. Laird, and Q. Shao The Protective Effect of Functional Connexin43 Channels on a Human Epithelial Cell Line Exposed to Oxidative Stress Invest. Ophthalmol. Vis. Sci., February 1, 2008; 49(2): 800 - 806. [Abstract] [Full Text] [PDF]

				S. Langlois, A. C. Maher, J. L. Manias, Q. Shao, G. M. Kidder, and D. W. Laird Connexin Levels Regulate Keratinocyte Differentiation in the Epidermis J. Biol. Chem., October 12, 2007; 282(41): 30171 - 30180. [Abstract] [Full Text] [PDF]

				X.-Q. Gong, Q. Shao, S. Langlois, D. Bai, and D. W. Laird Differential Potency of Dominant Negative Connexin43 Mutants in Oculodentodigital Dysplasia J. Biol. Chem., June 29, 2007; 282(26): 19190 - 19202. [Abstract] [Full Text] [PDF]

				J. Kalra, Q. Shao, H. Qin, T. Thomas, M. A. Alaoui-Jamali, and D. W. Laird Cx26 inhibits breast MDA-MB-435 cell tumorigenic properties by a gap junctional intercellular communication-independent mechanism Carcinogenesis, December 1, 2006; 27(12): 2528 - 2537. [Abstract] [Full Text] [PDF]

				X.-Q. Gong, Q. Shao, C. S. Lounsbury, D. Bai, and D. W. Laird Functional Characterization of a GJA1 Frameshift Mutation Causing Oculodentodigital Dysplasia and Palmoplantar Keratoderma J. Biol. Chem., October 20, 2006; 281(42): 31801 - 31811. [Abstract] [Full Text] [PDF]

				E. McLachlan, Q. Shao, H.-l. Wang, S. Langlois, and D. W. Laird Connexins Act as Tumor Suppressors in Three-dimensional Mammary Cell Organoids by Regulating Differentiation and Angiogenesis. Cancer Res., October 15, 2006; 66(20): 9886 - 9894. [Abstract] [Full Text] [PDF]

				A. Lai, D.-N. Le, W. A. Paznekas, W. D. Gifford, E. W. Jabs, and A. C. Charles Oculodentodigital dysplasia connexin43 mutations result in non-functional connexin hemichannels and gap junctions in C6 glioma cells J. Cell Sci., February 1, 2006; 119(3): 532 - 541. [Abstract] [Full Text] [PDF]

				A. M. Flenniken, L. R. Osborne, N. Anderson, N. Ciliberti, C. Fleming, J. E. I. Gittens, X.-Q. Gong, L. B. Kelsey, C. Lounsbury, L. Moreno, et al. A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia Development, October 1, 2005; 132(19): 4375 - 4386. [Abstract] [Full Text] [PDF]

				T. Thomas, K. Jordan, J. Simek, Q. Shao, C. Jedeszko, P. Walton, and D. W. Laird Mechanisms of Cx43 and Cx26 transport to the plasma membrane and gap junction regeneration J. Cell Sci., October 1, 2005; 118(19): 4451 - 4462. [Abstract] [Full Text] [PDF]

				J. Maza, J. D. Sarma, and M. Koval Defining a Minimal Motif Required to Prevent Connexin Oligomerization in the Endoplasmic Reticulum J. Biol. Chem., June 3, 2005; 280(22): 21115 - 21121. [Abstract] [Full Text] [PDF]

				Q. Shao, H. Wang, E. McLachlan, G. I.L. Veitch, and D. W. Laird Down-regulation of Cx43 by Retroviral Delivery of Small Interfering RNA Promotes an Aggressive Breast Cancer Cell Phenotype Cancer Res., April 1, 2005; 65(7): 2705 - 2711. [Abstract] [Full Text] [PDF]

				W.-L. Di, Y. Gu, J. E. A. Common, T. Aasen, E. A. O'Toole, D. P. Kelsell, and D. Zicha Connexin interaction patterns in keratinocytes revealed morphologically and by FRET analysis J. Cell Sci., April 1, 2005; 118(7): 1505 - 1514. [Abstract] [Full Text] [PDF]

				W. Roscoe, G. I. L. Veitch, X.-Q. Gong, E. Pellegrino, D. Bai, E. McLachlan, Q. Shao, G. M. Kidder, and D. W. Laird Oculodentodigital Dysplasia-causing Connexin43 Mutants Are Non-functional and Exhibit Dominant Effects on Wild-type Connexin43 J. Biol. Chem., March 25, 2005; 280(12): 11458 - 11466. [Abstract] [Full Text] [PDF]