Ability of a Connexin Chaperone to Rescue Oculodentodigital Dysplasia Mutant Connexin 43 Público

Pham, Huyen Tran Thi (2010)

Permanent URL: https://etd.library.emory.edu/concern/etds/bc386j51b?locale=es


Connexin 43 (Cx43) is a widely expressed gap junction protein responsible for forming multimeric channels enabling communication between two adjacent cells. Mutations in the GJA1 gene, which encodes for Cx43, can lead to physiological pathology as well as functional impairment at the cellular level. Oculodentodigital dysplasia (ODDD) is an autosomal dominant disorder resulting from mutations in the GJA1 gene. Characterization of the ODDD mutants G60S in the first extracellular loop, G138R in the intracellular loop, and R202H in the second extracellular loop indicates that most Cx43 proteins carrying these mutants localized in the endoplasmic reticulum (ER) or Golgi complex. Treatment of HeLa cells transiently transfected with ODDD mutants with the chemical chaperone 4-phenylbutyrate modulated Cx43 expression. However, trafficking of the mutant proteins were not altered by 4-PBA. Overexpression of the molecular chaperone ERp29, localized in the ER, was able to rescue the transport of G60S to the plasma membrane, but not the G138R or R202H mutants. These results suggest a differential effect of ERp29 on Cx43 mutants that may depend on the site of the mutation.

Table of Contents

I. List of Figures

II. List of Abbreviations

III. Introduction 1
a. Structure and Assembly of Connexins 1
b. Connexin43 Pathophysiology 3
c. Chaperones and Mutant Transmembrane Proteins 5

IV. Materials and Methods 7
a. Antibodies and Reagents 7
b. Cell Culture 7
c. Transfection 7
d. 4-PBA Treatment 8
e. Lentiviral Vector Transduction 8

V. Results 9

VI. Discussion 15

VII. References 17

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