This Article Full Text Full Text (PDF) All Versions of this Article: 96/10/e83    most recent 01.RES.0000168369.79972.d2v1 Alert me when this article is cited 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 Shibayama, J. Articles by Musa, H. Search for Related Content PubMed PubMed Citation Articles by Shibayama, J. Articles by Musa, H. Related Collections Genetics of cardiovascular disease Cell biology/structural biology Developmental biology Ion channels/membrane transport

(Circulation Research. 2005;96:e83.)
© 2005 American Heart Association, Inc.

UltraRapid Communications

Functional Characterization of Connexin43 Mutations Found in Patients With Oculodentodigital Dysplasia

Junko Shibayama, William Paznekas, Akiko Seki, Steven Taffet, Ethylin Wang Jabs, Mario Delmar, Hassan Musa

From the Departments of Pharmacology (J.S., A.S., M.D., H.M.), and Microbiology/Immunology (S.T.), S.U.N.Y. Upstate Medical University, Syracuse, NY 13210. Institute of Genetic Medicine, Department of Pediatrics (W.P., E.W.), and Medicine and Surgery (E.W.), Johns Hopkins University School of Medicine, Baltimore, MD.

Correspondence to Dr Hassan Musa. Department of Pharmacology Upstate Medical University, SUNY, 750 E. Adams St., Weiskotten Hall, Rm 3135, Syracuse, NY 13210. E-mail musah{at}upstate.edu

Specific mutations in GJA1, the gene encoding the gap junction protein connexin43 (Cx43), cause an autosomal dominant disorder called oculodentodigital dysplasia (ODDD). Here, we characterize the effects of 8 of these mutations on Cx43 function. Immunochemical studies have shown that most of the mutant proteins formed gap junction plaques at the sites of cell-cell apposition. However, 2 of the mutations (a codon duplication in the first extracellular loop, F52dup, and a missense mutation in the second extracellular loop, R202H, produced full-length connexins that failed to properly form gap junction plaques. Cx43 proteins containing ODDD mutations found in the N-terminus (Y17S), first transmembrane domain (G21R, A40V), second transmembrane domain (L90V), and cytoplasmic loop (I130T, K134E) do form gap junction plaques but show compromised channel function. L90V, I130T, and K134E demonstrated a significant decrease in junctional conductance relative to Cx43WT. Mutations Y17S, G21R, and A40V demonstrated a complete lack of functional electrical coupling even in the presence of significant plaque formation between paired cells. Heterologous channels formed by coexpression of Cx43WT and mutation R202H resulted in electrically functional gap junctions that were not permeable to Lucifer yellow. Therefore, the mutations found in ODDD not only cause phenotypic variability, but also result in various functional consequences. Overall, our data show an extensive range of molecular phenotypes, consistent with the pleiotropic nature of the clinical syndrome as a whole.

Key Words: connexin43 • ODDD • gap junctions

This article has been cited by other articles:

				B. C. Thomas, P. J. Minogue, V. Valiunas, G. Kanaporis, P. R. Brink, V. M. Berthoud, and E. C. Beyer Cataracts Are Caused by Alterations of a Critical N-Terminal Positive Charge in Connexin50 Invest. Ophthalmol. Vis. Sci., June 1, 2008; 49(6): 2549 - 2556. [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]

				N. Kalcheva, J. Qu, N. Sandeep, L. Garcia, J. Zhang, Z. Wang, P. D. Lampe, S. O. Suadicani, D. C. Spray, and G. I. Fishman Gap junction remodeling and cardiac arrhythmogenesis in a murine model of oculodentodigital dysplasia PNAS, December 18, 2007; 104(51): 20512 - 20516. [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]

				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]

				D. J. Chung, C. H. M. Castro, M. Watkins, J. P. Stains, M. Y. Chung, V. L. Szejnfeld, K. Willecke, M. Theis, and R. Civitelli Low peak bone mass and attenuated anabolic response to parathyroid hormone in mice with an osteoblast-specific deletion of connexin43 J. Cell Sci., October 15, 2006; 119(20): 4187 - 4198. [Abstract] [Full Text] [PDF]