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Specific functional pathologies of Cx43 mutations associated with oculodentodigital dysplasia.
Mol Biol Cell. 2016 07 15; 27(14):2172-85.MB

Abstract

Oculodentodigital dysplasia (ODDD) is a rare genetic disease that affects the development of multiple organs in the human body. More than 70 mutations in the gap junction connexin43 (Cx43) gene, GJA1, are associated with ODDD, most of which are inherited in an autosomal dominant manner. Many patients exhibit similar clinical presentations. However, there is high intrafamilial and interfamilial phenotypic variability. To better understand this variability, we established primary human dermal fibroblast cultures from several ODDD patients and unaffected controls. In the present study, we characterized three fibroblast lines expressing heterozygous p.L7V, p.G138R, and p.G143S Cx43 variants. All ODDD fibroblasts exhibited slower growth, reduced migration, and defective cell polarization, traits common to all ODDD fibroblasts studied so far. However, we found striking differences in overall expression levels, with p.L7V down-regulated at the mRNA and protein level. Although all of the Cx43 variants could traffic to the cell surface, there were stark differences in gap junction plaque formation, gap junctional intercellular communication, Cx43 phosphorylation, and hemichannel activity among Cx43 variants, as well as subtle differences in myofibroblast differentiation. Together these findings enabled us to discover mutation-specific pathologies that may help to predict future clinical outcomes.

Authors+Show Affiliations

Anatomy and Cell Biology, University of Western Ontario, London, ON N6A 5C1, Canada.Anatomy and Cell Biology, University of Western Ontario, London, ON N6A 5C1, Canada.Anatomy and Cell Biology, University of Western Ontario, London, ON N6A 5C1, Canada.Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Johns Hopkins University, Baltimore, MD 21205.Department of Neurology, Stanford University Medical Center, Palo Alto, CA 94304.Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, Helsinki 00290, Finland.Physiology and Pharmacology, University of Western Ontario, London, ON N6A 5C1, Canada.Anatomy and Cell Biology, University of Western Ontario, London, ON N6A 5C1, Canada Physiology and Pharmacology, University of Western Ontario, London, ON N6A 5C1, Canada Dale.Laird@schulich.uwo.ca.

Pub Type(s)

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

Language

eng

PubMed ID

27226478

Citation

Kelly, John J., et al. "Specific Functional Pathologies of Cx43 Mutations Associated With Oculodentodigital Dysplasia." Molecular Biology of the Cell, vol. 27, no. 14, 2016, pp. 2172-85.
Kelly JJ, Esseltine JL, Shao Q, et al. Specific functional pathologies of Cx43 mutations associated with oculodentodigital dysplasia. Mol Biol Cell. 2016;27(14):2172-85.
Kelly, J. J., Esseltine, J. L., Shao, Q., Jabs, E. W., Sampson, J., Auranen, M., Bai, D., & Laird, D. W. (2016). Specific functional pathologies of Cx43 mutations associated with oculodentodigital dysplasia. Molecular Biology of the Cell, 27(14), 2172-85. https://doi.org/10.1091/mbc.E16-01-0062
Kelly JJ, et al. Specific Functional Pathologies of Cx43 Mutations Associated With Oculodentodigital Dysplasia. Mol Biol Cell. 2016 07 15;27(14):2172-85. PubMed PMID: 27226478.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Specific functional pathologies of Cx43 mutations associated with oculodentodigital dysplasia. AU - Kelly,John J, AU - Esseltine,Jessica L, AU - Shao,Qing, AU - Jabs,Ethylin Wang, AU - Sampson,Jacinda, AU - Auranen,Mari, AU - Bai,Donglin, AU - Laird,Dale W, Y1 - 2016/05/25/ PY - 2016/01/27/received PY - 2016/05/20/accepted PY - 2016/5/27/entrez PY - 2016/5/27/pubmed PY - 2017/8/9/medline SP - 2172 EP - 85 JF - Molecular biology of the cell JO - Mol. Biol. Cell VL - 27 IS - 14 N2 - Oculodentodigital dysplasia (ODDD) is a rare genetic disease that affects the development of multiple organs in the human body. More than 70 mutations in the gap junction connexin43 (Cx43) gene, GJA1, are associated with ODDD, most of which are inherited in an autosomal dominant manner. Many patients exhibit similar clinical presentations. However, there is high intrafamilial and interfamilial phenotypic variability. To better understand this variability, we established primary human dermal fibroblast cultures from several ODDD patients and unaffected controls. In the present study, we characterized three fibroblast lines expressing heterozygous p.L7V, p.G138R, and p.G143S Cx43 variants. All ODDD fibroblasts exhibited slower growth, reduced migration, and defective cell polarization, traits common to all ODDD fibroblasts studied so far. However, we found striking differences in overall expression levels, with p.L7V down-regulated at the mRNA and protein level. Although all of the Cx43 variants could traffic to the cell surface, there were stark differences in gap junction plaque formation, gap junctional intercellular communication, Cx43 phosphorylation, and hemichannel activity among Cx43 variants, as well as subtle differences in myofibroblast differentiation. Together these findings enabled us to discover mutation-specific pathologies that may help to predict future clinical outcomes. SN - 1939-4586 UR - https://www.unboundmedicine.com/medline/citation/27226478/Specific_functional_pathologies_of_Cx43_mutations_associated_with_oculodentodigital_dysplasia_ L2 - https://www.molbiolcell.org/doi/full/10.1091/mbc.E16-01-0062?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -