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Intracellular distribution, assembly and effect of disease-associated connexin 31 mutants in HeLa cells.

Abstract
Mutations in connexin 31 (Cx31) are associated with erythrokeratodermia variabilis (EKV), hearing impairment and peripheral neuropathy; however, the pathological mechanism of Cx31 mutants remains unknown. This study analyzed 11 disease-associated Cx31 variants and one non-disease-associated Cx31 variant and compared their intracellular distribution and assembly in HeLa cells and their effect on these cells. The fluorescent localization assay showed no gap junction plaque formation in the cells expressing the recessive EKV-associated mutant (L34P) and four hearing impairment-associated mutants (66delD, 141delI, R180X and E183K), significantly reduced plaque formation in the cells with five EKV-associated dominant mutants (G12R, G12D, R42P, C86S and F137L) and no obvious change in the cells with two other mutants (I141V and 652del12). Immunoblotting analysis showed that 12 mutated Cx31s, like WT-Cx31, are able to form the Triton X-100 insoluble complex; however, the quantity of Triton X-100 insoluble complex in the transfected HeLa cells varied among different Cx31 mutants. Additionally, the expression of five EKV-associated dominant mutants (G12R, G12D, R42P, C86S and F137L) caused cell death in HeLa cells. However, the five hearing impairment-associated mutants did not induce cell death. The above results suggest that disease-associated mutants gain deleterious functions differentially. In summary, disease-associated Cx31 mutants impair the formation of normal gap junctions at different levels, and the diseases associated with Cx31 mutations may result from the abnormal assembly, trafficking and metabolism of the Cx31 mutants.
AuthorsLi-Qiang He, Yu Liu, Fang Cai, Zhi-Ping Tan, Qian Pan, De-Sheng Liang, Zhi-Gao Long, Ling-Qian Wu, Liang-Qun Huang, He-Ping Dai, Kun Xia, Jia-Hui Xia, Zhuo-Hua Zhang
JournalActa biochimica et biophysica Sinica (Acta Biochim Biophys Sin (Shanghai)) Vol. 37 Issue 8 Pg. 547-54 (Aug 2005) ISSN: 1672-9145 [Print] China
PMID16077902 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Connexins
  • Recombinant Proteins
  • GJB3 protein, human
Topics
  • Apoptosis
  • Connexins (genetics, metabolism)
  • Erythema (genetics, metabolism)
  • Gap Junctions (metabolism)
  • HeLa Cells
  • Hearing Disorders (genetics, metabolism)
  • Humans
  • Keratosis (genetics, metabolism)
  • Mutation
  • Peripheral Nervous System Diseases (genetics, metabolism)
  • Protein Transport
  • Recombinant Proteins (metabolism)
  • Subcellular Fractions (metabolism)

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