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J. Biol. Chem., Vol. 280, Issue 49, 40788-40795, December 9, 2005

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An Aberrant Sequence in a Connexin46 Mutant Underlies Congenital Cataracts^*

Peter J. Minogue, Xiaoqin Liu, Lisa Ebihara, Eric C. Beyer, and Viviana M. Berthoud1

From the Department of Pediatrics, University of Chicago, Chicago, Illinois 60637 and the Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064

An increasing number of diseases have been mapped to genes coding for ion channel proteins, including the gap junction proteins, connexins. Here, we report on the identification of an amino acid sequence underlying the behavior of a non-functional mutant connexin46 (CX46) associated with congenital cataracts. The mutant protein, CX46fs380, is 31 amino acids longer than CX46 and contains 87 aberrant amino acids in its C terminus. When expressed in mammalian cells, the mutant CX46 was not found at gap junctional plaques, but it showed extensive co-localization with markers for ERGIC and Golgi. The severe reductions in function and formation of gap junctional plaques were transferred to other connexins by creating chimeras containing the last third (or more) of the aberrant C terminus of the CX46 mutant. This sequence also impaired trafficking of a CD8 chimera. Site-directed mutagenesis of a diphenylalanine restored appositional membrane localization and function. These results suggest a novel mechanism in which a mutation causes disease by generating a motif that leads to retention within the synthetic/secretory pathway.

Received for publication, May 2, 2005 , and in revised form, September 19, 2005.

^* This work was supported by National Institutes of Health Grants EY08368 (to E. C. B.) and EY10589 (to L. E.). 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.

¹ To whom correspondence should be addressed: Dept. of Pediatrics, Section of Hematology/Oncology, University of Chicago, 5841 S. Maryland Ave., MC 4060, Chicago, IL 60637. Tel.: 773-702-6808; Fax: 773-702-9881; E-mail: vberthou{at}peds.bsd.uchicago.edu.

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