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Autosomal recessive GJA1 (Cx43) gene mutations cause oculodentodigital dysplasia by distinct mechanisms.
J Cell Sci. 2013 Jul 01; 126(Pt 13):2857-66.JC

Abstract

Oculodentodigital dysplasia (ODDD) is mainly an autosomal dominant human disease caused by mutations in the GJA1 gene, which encodes the gap junction protein connexin43 (Cx43). Surprisingly, there have been two autosomal recessive mutations reported that cause ODDD: a single amino acid substitution (R76H) and a premature truncation mutation (R33X). When expressed in either gap junctional intercellular communication (GJIC)-deficient HeLa cells or Cx43-expressing NRK cells, the R76H mutant trafficked to the plasma membrane to form gap junction-like plaques, whereas the R33X mutant remained diffusely localized throughout the cell, including the nucleus. As expected, the R33X mutant failed to form functional channels. In the case of the R76H mutant, dye transfer studies in HeLa cells and electrical conductance analysis in GJIC-deficient N2a cells revealed that this mutant could form functional gap junction channels, albeit with reduced macroscopic and single channel conductance. Alexa 350 dye transfer studies further revealed that the R76H mutant had no detectable negative effect on the function of co-expressed Cx26, Cx32, Cx37 or Cx40, whereas the R33X mutant exhibited significant dominant or trans-dominant effects on Cx43 and Cx40 as manifested by a reduction in wild-type connexin gap junction plaques. Taken together, our results suggest that the trans-dominant effect of R33X together with its complete inability to form a functional channel may explain why patients harboring this autosomal recessive R33X mutant exhibit greater disease burden than patients harboring the R76H mutant.

Authors+Show Affiliations

Department of Anatomy and Cell Biology, University of Western Ontario, London ON N6A-5C1, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23606748

Citation

Huang, Tao, et al. "Autosomal Recessive GJA1 (Cx43) Gene Mutations Cause Oculodentodigital Dysplasia By Distinct Mechanisms." Journal of Cell Science, vol. 126, no. Pt 13, 2013, pp. 2857-66.
Huang T, Shao Q, MacDonald A, et al. Autosomal recessive GJA1 (Cx43) gene mutations cause oculodentodigital dysplasia by distinct mechanisms. J Cell Sci. 2013;126(Pt 13):2857-66.
Huang, T., Shao, Q., MacDonald, A., Xin, L., Lorentz, R., Bai, D., & Laird, D. W. (2013). Autosomal recessive GJA1 (Cx43) gene mutations cause oculodentodigital dysplasia by distinct mechanisms. Journal of Cell Science, 126(Pt 13), 2857-66. https://doi.org/10.1242/jcs.123315
Huang T, et al. Autosomal Recessive GJA1 (Cx43) Gene Mutations Cause Oculodentodigital Dysplasia By Distinct Mechanisms. J Cell Sci. 2013 Jul 1;126(Pt 13):2857-66. PubMed PMID: 23606748.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Autosomal recessive GJA1 (Cx43) gene mutations cause oculodentodigital dysplasia by distinct mechanisms. AU - Huang,Tao, AU - Shao,Qing, AU - MacDonald,Andrew, AU - Xin,Li, AU - Lorentz,Robert, AU - Bai,Donglin, AU - Laird,Dale W, Y1 - 2013/04/19/ PY - 2013/4/23/entrez PY - 2013/4/23/pubmed PY - 2014/1/17/medline KW - Cx43 KW - GJA1 KW - Gap junctions KW - Oculodentodigital dysplasia SP - 2857 EP - 66 JF - Journal of cell science JO - J. Cell. Sci. VL - 126 IS - Pt 13 N2 - Oculodentodigital dysplasia (ODDD) is mainly an autosomal dominant human disease caused by mutations in the GJA1 gene, which encodes the gap junction protein connexin43 (Cx43). Surprisingly, there have been two autosomal recessive mutations reported that cause ODDD: a single amino acid substitution (R76H) and a premature truncation mutation (R33X). When expressed in either gap junctional intercellular communication (GJIC)-deficient HeLa cells or Cx43-expressing NRK cells, the R76H mutant trafficked to the plasma membrane to form gap junction-like plaques, whereas the R33X mutant remained diffusely localized throughout the cell, including the nucleus. As expected, the R33X mutant failed to form functional channels. In the case of the R76H mutant, dye transfer studies in HeLa cells and electrical conductance analysis in GJIC-deficient N2a cells revealed that this mutant could form functional gap junction channels, albeit with reduced macroscopic and single channel conductance. Alexa 350 dye transfer studies further revealed that the R76H mutant had no detectable negative effect on the function of co-expressed Cx26, Cx32, Cx37 or Cx40, whereas the R33X mutant exhibited significant dominant or trans-dominant effects on Cx43 and Cx40 as manifested by a reduction in wild-type connexin gap junction plaques. Taken together, our results suggest that the trans-dominant effect of R33X together with its complete inability to form a functional channel may explain why patients harboring this autosomal recessive R33X mutant exhibit greater disease burden than patients harboring the R76H mutant. SN - 1477-9137 UR - https://www.unboundmedicine.com/medline/citation/23606748/Autosomal_recessive_GJA1__Cx43__gene_mutations_cause_oculodentodigital_dysplasia_by_distinct_mechanisms_ L2 - http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=23606748 DB - PRIME DP - Unbound Medicine ER -