Mutations of two genes that encode gap junction proteins that are expressed in the lens (CX46 and CX50) are among the most frequent genetic causes of congenital cataracts. Our previous studies of a variety of cataract-associated connexin mutants (predominantly through expression in Xenopus oocytes or transfected mammalian cell lines) have shown that most of these connexin mutants are not functional (and sometimes act as dominant negative inhibitors of their wild type counterparts). Moreover, many of these mutants exhibit one of two types of abnormal cellular behaviors: (1) they accumulate in cytoplasmic inclusions and appear to be resistant to degradation or (2) they do not traffic properly to the plasma membrane and localize within the secretory pathway. We hypothesize that lens cells expressing mutant connexins that form cytoplasmic inclusions or are retained within the secretory pathway will exhibit unique abnormalities due to abnormal interactions (or lack of interactions) of the connexin mutants with lens-specific proteins causing their retention, altered abundance, or decreased function. Experiments are proposed to study representative members of each class of connexin mutants in lens cells (of chicken embryos, stably transfected lens epithelial cell lines, or lenses of mice carrying connexin mutations). A repertoire of microscopy, cell biological and biochemical approaches will be used to address two central questions: """""""" What are the fates of the mutant connexins in the lens? """""""" What are the consequences of expression of the mutant connexins upon other lens components? The data obtained from these studies are likely to have broad implications towards understanding cataract formation in general, since similar cellular abnormalities (formation of inclusions and retention in the biosynthetic pathway) have also been observed for many other cataract-associated mutant proteins.

Public Health Relevance

Cataracts are the major cause of blindness worldwide and are a major cause of visual impairment in the United States. Mutations of two genes that encode gap junction proteins (CX46 and CX50) that are expressed in the lens are among the most frequent genetic causes of congenital cataracts. Studies are proposed to elucidate the cellular and biochemical basis of cataracts due to these mutant connexins.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Special Emphasis Panel (ZRG1)
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Araj, Houmam H
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University of Chicago
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Berthoud, Viviana M; Minogue, Peter J; Lambert, Paul A et al. (2016) The Cataract-linked Mutant Connexin50D47A Causes Endoplasmic Reticulum Stress in Mouse Lenses. J Biol Chem 291:17569-78
Berthoud, Viviana M; Minogue, Peter J; Snabb, Joseph I et al. (2016) Connexin23 deletion does not affect lens transparency. Exp Eye Res 146:283-8
Beyer, Eric C (2015) Are these connexins compatible and does it matter? Channels (Austin) 9:63-4
Tong, Jun-Jie; Minogue, Peter J; Kobeszko, Matthew et al. (2015) The connexin46 mutant, Cx46T19M, causes loss of gap junction function and alters hemi-channel gating. J Membr Biol 248:145-55
Berthoud, Viviana M; Minogue, Peter J; Osmolak, Patricia et al. (2014) Roles and regulation of lens epithelial cell connexins. FEBS Lett 588:1297-303
Falk, Matthias M; Kells, Rachael M; Berthoud, Viviana M (2014) Degradation of connexins and gap junctions. FEBS Lett 588:1221-9
Berthoud, Viviana M; Minogue, Peter J; Yu, Helena et al. (2014) Connexin46fs380 causes progressive cataracts. Invest Ophthalmol Vis Sci 55:6639-48
Senthil Kumar, G; Kyle, John W; Minogue, Peter J et al. (2013) An MIP/AQP0 mutation with impaired trafficking and function underlies an autosomal dominant congenital lamellar cataract. Exp Eye Res 110:136-41
Beyer, Eric C; Ebihara, Lisa; Berthoud, Viviana M (2013) Connexin mutants and cataracts. Front Pharmacol 4:43
Minogue, Peter J; Beyer, Eric C; Berthoud, Viviana M (2013) A connexin50 mutant, CX50fs, that causes cataracts is unstable, but is rescued by a proteasomal inhibitor. J Biol Chem 288:20427-34

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