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. 2024 Dec 13;12:RP90419. doi: 10.7554/eLife.90419

Figure 1. Rare putative LOF (pLOF) variants in SLC39A5 are associated with elevated serum zinc and nominal protection against type II diabetes (T2D).

(A) Serum zinc in carriers of SLC39A5 pLOF variants in the discovery cohort. Controls (Ref; SLC39A5+/+) and heterozygous carriers of pLOF variant alleles in SLC39A5 (Het; SLC39A5+/-). Subject numbers: Ref and Het, respectively: n=5317 and n=15. (B) Trans-ancestry meta-analysis of the association of SLC39A5 pLOF variants with T2D. (C–I) Serum zinc and insulin profile of age, sex and BMI-matched controls in serum call back study. Subject numbers: Ref and Het, respectively: n=246–253 and n=86–91, **p<0.01, unpaired t-test. Numeric data is summarized in Supplementary file 1.

Figure 1.

Figure 1—figure supplement 1. Graphic abstract.

Figure 1—figure supplement 1.

Heterozygous loss-of-function mutations in SLC39A5 are associated with elevated circulating zinc levels and nominal reduction in type II diabetes risk in humans. Loss of Slc39a5 results in elevated circulating and hepatic zinc levels in mice. Mice lacking Slc39a5 function are protected against hepatic steatosis and hyperglycemia resulting from diet-induced obesity or leptin-receptor deficiency and display reduced hepatic inflammation and fibrosis resulting from diet-induced non-alcoholic steatohepatitis (NASH). Loss of Slc39a5 function results in hepatic AMPK and AKT activation.
Figure 1—figure supplement 2. SLC39A5 putative LOF (pLOF) variants p.Y47*(c.141C>G), p.R311*(c.931C>T), and p.R322*(c.964C>T) encode for non-functional proteins.

Figure 1—figure supplement 2.

HEK293 cell transfected with expression constructs encoding SLC39A5 wild-type (WT), Y47*, R311*, and R322* variants. (A, B) Immunostaining and FACS analysis demonstrating WT SLC39A5 localization to the cell surface. Scale bar, 10 um. (C) Overexpression of WT SLC39A5 results in Zn2 + mediated MRE activation in a dose-dependent manner, n=4. (D) FACS analyses demonstrate that cell surface expression of SLC39A5 Y47*, R311*, and R322* muteins is markedly reduced. (E) Variants Y47*, R311*, and R322* did not mediate Zn2 + induction of MRE, n=8, Statistical comparison to Mock and WT, respectively: ***p<0.001, ###p<0.001, two-way ANOVA with post hoc Tukey’s test. Metal regulatory element (MRE), firefly luciferase (Fluc), renilla luciferase (Rluc), cytomegalovirus (CMV), gene of interest (GOI), internal ribosome entry site (IRES).