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Gain-of-Function Claims for Type-2-Diabetes-Associated Coding Variants in SLC16A11 Are Not Supported by the Experimental Data
Human genetic variants in SLC16A11 are associated with increased risk of type 2 diabetes (T2D). We previously identified two distinct mechanisms through which co-inherited T2D-risk coding and non-coding variants disrupt SLC16A11 expression and activity, thus implicating reduced SLC16A11 function as...
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Published in: | Cell reports (Cambridge) 2019-10, Vol.29 (3), p.778-780 |
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Main Authors: | , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Human genetic variants in SLC16A11 are associated with increased risk of type 2 diabetes (T2D). We previously identified two distinct mechanisms through which co-inherited T2D-risk coding and non-coding variants disrupt SLC16A11 expression and activity, thus implicating reduced SLC16A11 function as the disease-relevant direction of effect. In a recent publication, Zhao et al. (2019a) argue that human SLC16A11 coding variants confer gain of function, basing their conclusions on phenotypic changes observed following overexpression of mutant murine Slc16a11. However, data necessary to demonstrate gain-of-function activity are not reported. Furthermore, several fundamental flaws in their experimental system—including inaccurate modeling of the human variant haplotype and expression conditions that are not physiologically relevant—prevent conclusions about T2D-risk variant effects on human physiology. This Matters Arising paper is in response to Zhao et al. (2019a), published in Cell Reports. See also the response by Zhao et al. (2019b) in this issue of Cell Reports.
•The mutant model system used by Zhao et al. may not pertain to human SLC16A11 physiology•The mouse mutations tested do not correspond to the human SLC16A11 T2D-risk haplotype•Gain-of-function claims for Slc16a11 variants are not supported by data in the paper•Conclusions about physiological impact of human T2D variants are not justified
Hoch et al. discuss the analysis of coding variants of SLC16A11 in mice and humans in light of a recent Cell Reports publication. This Matters Arising paper is in response to Zhao et al. (2019a), published in Cell Reports. See also the response by Zhao et al. (2019b), published in this issue. |
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ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2019.09.021 |