Cargando…

Novel Adiponectin Variants Identified in Type 2 Diabetic Patients Reveal Multimerization and Secretion Defects

ADIPOQ, encoding adiponectin, is a candidate gene for type 2 diabetes (T2D) identified by genome-wide linkage analyses with supporting evidence showing the protein function in sensitizing insulin actions. In an endeavor to characterize candidate genes causing T2D in Thai patients, we identified 10 n...

Descripción completa

Detalles Bibliográficos
Autores principales: Jungtrakoon, Prapaporn, Plengvidhya, Nattachet, Tangjittipokin, Watip, Chimnaronk, Sarin, Salaemae, Wanisa, Chongjaroen, Nalinee, Chanprasert, Kanjana, Sujjitjoon, Jatuporn, Srisawat, Chatchawan, Yenchitsomanus, Pa-thai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202584/
https://www.ncbi.nlm.nih.gov/pubmed/22046359
http://dx.doi.org/10.1371/journal.pone.0026792
_version_ 1782215017636036608
author Jungtrakoon, Prapaporn
Plengvidhya, Nattachet
Tangjittipokin, Watip
Chimnaronk, Sarin
Salaemae, Wanisa
Chongjaroen, Nalinee
Chanprasert, Kanjana
Sujjitjoon, Jatuporn
Srisawat, Chatchawan
Yenchitsomanus, Pa-thai
author_facet Jungtrakoon, Prapaporn
Plengvidhya, Nattachet
Tangjittipokin, Watip
Chimnaronk, Sarin
Salaemae, Wanisa
Chongjaroen, Nalinee
Chanprasert, Kanjana
Sujjitjoon, Jatuporn
Srisawat, Chatchawan
Yenchitsomanus, Pa-thai
author_sort Jungtrakoon, Prapaporn
collection PubMed
description ADIPOQ, encoding adiponectin, is a candidate gene for type 2 diabetes (T2D) identified by genome-wide linkage analyses with supporting evidence showing the protein function in sensitizing insulin actions. In an endeavor to characterize candidate genes causing T2D in Thai patients, we identified 10 novel ADIPOQ variations, several of which were non-synonymous variations observed only in the patients. To examine the impact of these non-synonymous variations on adiponectin structure and biochemical characteristics, we conducted a structural analysis of the wild-type and variant proteins by in silico modeling and further characterized biochemical properties of the variants with predicted structural abnormalities from the modeling by molecular and biochemical studies. The recombinant plasmids containing wild-type and variant ADIPOQ cDNAs derived from the variations identified by our study (R55H, R112H, and R131H) and previous work (G90S and R112C) were constructed and transiently expressed and co-expressed in cultured HEK293T cells to investigate their oligomerization, interaction, and secretion. We found that the novel R55H variant impaired protein multimerization but it did not exert the effect over the co-expressed wild-type protein while novel R131H variant impaired protein secretion and also affected the co-expressed wild-type protein in a dominant negative fashion. The R131H variant could traffic from the endoplasmic reticulum to the Golgi, trans-Golgi network, and early endosome but could not be secreted. The R131H variant was likely to be degraded through the lysosomal system and inhibition of its degradation rescued the variant protein from secretion defect. We have shown the possibility of using in silico modeling for predicting the effect of amino acid substitution on adiponectin oligomerization. This is also the first report that demonstrates a dominant negative effect of the R131H variant on protein secretion and the possibility of using protein degradation inhibitors as therapeutic agents in the patients carrying adiponectin variants with secretion defect.
format Online
Article
Text
id pubmed-3202584
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-32025842011-11-01 Novel Adiponectin Variants Identified in Type 2 Diabetic Patients Reveal Multimerization and Secretion Defects Jungtrakoon, Prapaporn Plengvidhya, Nattachet Tangjittipokin, Watip Chimnaronk, Sarin Salaemae, Wanisa Chongjaroen, Nalinee Chanprasert, Kanjana Sujjitjoon, Jatuporn Srisawat, Chatchawan Yenchitsomanus, Pa-thai PLoS One Research Article ADIPOQ, encoding adiponectin, is a candidate gene for type 2 diabetes (T2D) identified by genome-wide linkage analyses with supporting evidence showing the protein function in sensitizing insulin actions. In an endeavor to characterize candidate genes causing T2D in Thai patients, we identified 10 novel ADIPOQ variations, several of which were non-synonymous variations observed only in the patients. To examine the impact of these non-synonymous variations on adiponectin structure and biochemical characteristics, we conducted a structural analysis of the wild-type and variant proteins by in silico modeling and further characterized biochemical properties of the variants with predicted structural abnormalities from the modeling by molecular and biochemical studies. The recombinant plasmids containing wild-type and variant ADIPOQ cDNAs derived from the variations identified by our study (R55H, R112H, and R131H) and previous work (G90S and R112C) were constructed and transiently expressed and co-expressed in cultured HEK293T cells to investigate their oligomerization, interaction, and secretion. We found that the novel R55H variant impaired protein multimerization but it did not exert the effect over the co-expressed wild-type protein while novel R131H variant impaired protein secretion and also affected the co-expressed wild-type protein in a dominant negative fashion. The R131H variant could traffic from the endoplasmic reticulum to the Golgi, trans-Golgi network, and early endosome but could not be secreted. The R131H variant was likely to be degraded through the lysosomal system and inhibition of its degradation rescued the variant protein from secretion defect. We have shown the possibility of using in silico modeling for predicting the effect of amino acid substitution on adiponectin oligomerization. This is also the first report that demonstrates a dominant negative effect of the R131H variant on protein secretion and the possibility of using protein degradation inhibitors as therapeutic agents in the patients carrying adiponectin variants with secretion defect. Public Library of Science 2011-10-26 /pmc/articles/PMC3202584/ /pubmed/22046359 http://dx.doi.org/10.1371/journal.pone.0026792 Text en Jungtrakoon et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Jungtrakoon, Prapaporn
Plengvidhya, Nattachet
Tangjittipokin, Watip
Chimnaronk, Sarin
Salaemae, Wanisa
Chongjaroen, Nalinee
Chanprasert, Kanjana
Sujjitjoon, Jatuporn
Srisawat, Chatchawan
Yenchitsomanus, Pa-thai
Novel Adiponectin Variants Identified in Type 2 Diabetic Patients Reveal Multimerization and Secretion Defects
title Novel Adiponectin Variants Identified in Type 2 Diabetic Patients Reveal Multimerization and Secretion Defects
title_full Novel Adiponectin Variants Identified in Type 2 Diabetic Patients Reveal Multimerization and Secretion Defects
title_fullStr Novel Adiponectin Variants Identified in Type 2 Diabetic Patients Reveal Multimerization and Secretion Defects
title_full_unstemmed Novel Adiponectin Variants Identified in Type 2 Diabetic Patients Reveal Multimerization and Secretion Defects
title_short Novel Adiponectin Variants Identified in Type 2 Diabetic Patients Reveal Multimerization and Secretion Defects
title_sort novel adiponectin variants identified in type 2 diabetic patients reveal multimerization and secretion defects
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202584/
https://www.ncbi.nlm.nih.gov/pubmed/22046359
http://dx.doi.org/10.1371/journal.pone.0026792
work_keys_str_mv AT jungtrakoonprapaporn noveladiponectinvariantsidentifiedintype2diabeticpatientsrevealmultimerizationandsecretiondefects
AT plengvidhyanattachet noveladiponectinvariantsidentifiedintype2diabeticpatientsrevealmultimerizationandsecretiondefects
AT tangjittipokinwatip noveladiponectinvariantsidentifiedintype2diabeticpatientsrevealmultimerizationandsecretiondefects
AT chimnaronksarin noveladiponectinvariantsidentifiedintype2diabeticpatientsrevealmultimerizationandsecretiondefects
AT salaemaewanisa noveladiponectinvariantsidentifiedintype2diabeticpatientsrevealmultimerizationandsecretiondefects
AT chongjaroennalinee noveladiponectinvariantsidentifiedintype2diabeticpatientsrevealmultimerizationandsecretiondefects
AT chanprasertkanjana noveladiponectinvariantsidentifiedintype2diabeticpatientsrevealmultimerizationandsecretiondefects
AT sujjitjoonjatuporn noveladiponectinvariantsidentifiedintype2diabeticpatientsrevealmultimerizationandsecretiondefects
AT srisawatchatchawan noveladiponectinvariantsidentifiedintype2diabeticpatientsrevealmultimerizationandsecretiondefects
AT yenchitsomanuspathai noveladiponectinvariantsidentifiedintype2diabeticpatientsrevealmultimerizationandsecretiondefects