HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Connexin mutation that causes dominant congenital cataracts inhibits gap junctions, but not hemichannels, in a dominant negative manner.

Abstract
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.
AuthorsEric A Banks, Masoud M Toloue, Qian Shi, Zifei Jade Zhou, Jialu Liu, Bruce J Nicholson, Jean X Jiang
JournalJournal of cell science (J Cell Sci) Vol. 122 Issue Pt 3 Pg. 378-88 (Feb 01 2009) ISSN: 0021-9533 [Print] England
PMID19126675 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Connexins
  • Eye Proteins
  • connexin 50
Topics
  • 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

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: