Document Detail


Connexin mutation that causes dominant congenital cataracts inhibits gap junctions, but not hemichannels, in a dominant negative manner.
MedLine Citation:
PMID:  19126675     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The connexin (Cx) 50, E48K, mutation is associated with a human dominant congenital cataract; however, the underlying molecular mechanism has not been characterized. The glutamate (E) residue at position 48 is highly conserved across animal species and types of connexins. When expressed in paired Xenopus oocytes, human (h) and chicken (ch) Cx50 E48K mutants showed no electrical coupling. In addition, this mutation acts in a dominant negative manner when paired hetero-typically or hetero-merically with wild-type Cx50, but has no such effect on Cx46, the other lens fiber connexin. A similar loss-of-function and dominant negative effect was observed using dye transfer assays in the same system. By using two different dye transfer methods, with two different tracer dyes, we found chCx50 E48K expressed in chicken lens embryonic fibroblast cells by retroviral infection similarly failed to induce dye coupling, and prevented wild-type chCx50 from forming functional gap junctions. In contrast to its effect on gap junctions, the E48K mutation has no effect on hemichannel activity when assayed using electrical conductance in oocytes, and mechanically induced dye uptake in cells. Cx50 is functionally involved in cell differentiation and lens development, and the E48K mutant promotes primary lens cell differentiation indistinguishable from wild-type chCx50, despite its lack of junctional channel function. Together the data show that mutations affecting gap junctions but not hemichannel function of Cx50 can lead to dominant congenital cataracts in humans. This clearly supports the model of intercellular coupling of fiber cells creating a microcirculation of nutrients and metabolites required for lens transparency.
Authors:
Eric A Banks; Masoud M Toloue; Qian Shi; Zifei Jade Zhou; Jialu Liu; Bruce J Nicholson; Jean X Jiang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-01-06
Journal Detail:
Title:  Journal of cell science     Volume:  122     ISSN:  0021-9533     ISO Abbreviation:  J. Cell. Sci.     Publication Date:  2009 Feb 
Date Detail:
Created Date:  2009-01-22     Completed Date:  2009-04-27     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  0052457     Medline TA:  J Cell Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  378-88     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229, USA.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Cataract / genetics,  metabolism*
Cattle
Chick Embryo
Connexins / genetics,  metabolism*
Eye Proteins / genetics,  metabolism*
Gap Junctions / genetics,  metabolism*
Genes, Dominant
Genetic Vectors
Humans
Lens, Crystalline / metabolism*
Mice
Molecular Sequence Data
Mutagenesis, Site-Directed
Mutation / genetics
Oocytes
Rats
Sequence Alignment
Transfection
Xenopus laevis
Grant Support
ID/Acronym/Agency:
EY12085/EY/NEI NIH HHS; GM55437/GM/NIGMS NIH HHS; P01AG19316/AG/NIA NIH HHS; P30 AG013319/AG/NIA NIH HHS; P30 CA54174/CA/NCI NIH HHS; R01 GM055437-15/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Connexins; 0/Eye Proteins; 0/connexin 50
Comments/Corrections

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