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(American Journal of Pathology. 2006;169:416-423.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051242

A Novel N14Y Mutation in Connexin26 in Keratitis-Ichthyosis-Deafness Syndrome

Analyses of Altered Gap Junctional Communication and Molecular Structure of N Terminus of Mutated Connexin26

Ken Arita^*, Masashi Akiyama^*, Tomoyasu Aizawa, Yoshitaka Umetsu, Ikuo Segawa, Maki Goto^*, Daisuke Sawamura^*, Makoto Demura, Keiichi Kawano and Hiroshi Shimizu^*

From the Department of Dermatology,^* Hokkaido University Graduate School of Medicine, Sapporo, Japan; Laboratory of Structural Bio-Macromolecular Science III, Division of Biological Science, Hokkaido University, Sapporo, Japan; and the Department of Dermatology, Iwate Prefectural Central Hospital, Iwate, Japan

Connexins (Cxs) are transmembranous proteins that connect adjacent cells via channels known as gap junctions. The N-terminal 21 amino acids of Cx26 are located at the cytoplasmic side of the channel pore and are thought to be essential for the regulation of channel selectivity. We have found a novel mutation, N14Y, in the N-terminal domain of Cx26 in a case of keratitis-ichthyosis-deafness syndrome. Reduced gap junctional intercellular communication was observed in the patient’s keratinocytes by the dye transfer assay using scrape-loading methods. The effect of this mutation on molecular structure was investigated using synthetic N-terminal peptides from both wild-type and mutated Cx26. Two-dimensional ¹H nuclear magnetic resonance and circular dichroism measurements demonstrated that the secondary structures of these two model peptides are similar to each other. However, several novel nuclear Overhauser effect signals appeared in the N14Y mutant, and the secondary structure of the mutant peptide was more susceptible to induction of 2,2,2-trifluoroethanol than wild type. Thus, it is likely that the N14Y mutation induces a change in local structural flexibility of the N-terminal domain, which is important for exerting the activity of the channel function, resulting in impaired gap junctional intercellular communication.

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