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Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.

ABSTRACT: Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.

SUBMITTER: Flannick J

PROVIDER: S-EPMC4051628 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.

Flannick Jason J Thorleifsson Gudmar G Beer Nicola L NL Jacobs Suzanne B R SB Grarup Niels N Burtt Noël P NP Mahajan Anubha A Fuchsberger Christian C Atzmon Gil G Benediktsson Rafn R Blangero John J Bowden Don W DW Brandslund Ivan I Brosnan Julia J Burslem Frank F Chambers John J Cho Yoon Shin YS Christensen Cramer C Douglas Desirée A DA Duggirala Ravindranath R Dymek Zachary Z Farjoun Yossi Y Fennell Timothy T Fontanillas Pierre P Forsén Tom T Gabriel Stacey S Glaser Benjamin B Gudbjartsson Daniel F DF Hanis Craig C Hansen Torben T Hreidarsson Astradur B AB Hveem Kristian K Ingelsson Erik E Isomaa Bo B Johansson Stefan S Jørgensen Torben T Jørgensen Marit Eika ME Kathiresan Sekar S Kong Augustine A Kooner Jaspal J Kravic Jasmina J Laakso Markku M Lee Jong-Young JY Lind Lars L Lindgren Cecilia M CM Linneberg Allan A Masson Gisli G Meitinger Thomas T Mohlke Karen L KL Molven Anders A Morris Andrew P AP Potluri Shobha S Rauramaa Rainer R Ribel-Madsen Rasmus R Richard Ann-Marie AM Rolph Tim T Salomaa Veikko V Segrè Ayellet V AV Skärstrand Hanna H Steinthorsdottir Valgerdur V Stringham Heather M HM Sulem Patrick P Tai E Shyong ES Teo Yik Ying YY Teslovich Tanya T Thorsteinsdottir Unnur U Trimmer Jeff K JK Tuomi Tiinamaija T Tuomilehto Jaakko J Vaziri-Sani Fariba F Voight Benjamin F BF Wilson James G JG Boehnke Michael M McCarthy Mark I MI Njølstad Pål R PR Pedersen Oluf O Groop Leif L Cox David R DR Stefansson Kari K Altshuler David D

Nature genetics 20140302 4

Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein- ...[more]

PMID: 24584071

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Project description:The human zinc transporter ZnT8 (SLC30A8) is expressed primarily in pancreatic β-cells and plays a key function in maintaining the concentration of blood glucose through its role in insulin storage, maturation and secretion. ZnT8 is an autoantigen for Type 1 diabetes (T1D) and is associated with Type 2 diabetes (T2D) through its risk allele that encodes a major non-synonymous single nucleotide polymorphism (SNP) at Arg325. Loss of function mutations improve insulin secretion and are protective against diabetes. Despite its role in diabetes and concomitant potential as a drug target, little is known about the structure or mechanism of ZnT8. To this end, we expressed ZnT8 in Pichia pastoris yeast and Sf9 insect cells. Guided by a rational screen of 96 detergents, we developed a method to solubilize and purify recombinant ZnT8. An in vivo transport assay in Pichia and a liposome-based uptake assay for insect-cell derived ZnT8 showed that the protein is functionally active in both systems. No significant difference in activity was observed between full-length ZnT8 (ZnT8A) and the amino-terminally truncated ZnT8B isoform. A fluorescence-based in vitro transport assay using proteoliposomes indicated that human ZnT8 functions as a Zn2+/H+ antiporter. We also purified E. coli-expressed amino- and carboxy-terminal cytoplasmic domains of ZnT8A. Circular dichroism spectrometry suggested that the amino-terminal domain contains predominantly α-helical structure, and indicated that the carboxy-terminal domain has a mixed α/β structure. Negative-stain electron microscopy and single-particle image analysis yielded a density map of ZnT8B at 20 Å resolution, which revealed that ZnT8 forms a dimer in detergent micelles. Two prominent lobes are ascribed to the transmembrane domains, and the molecular envelope recapitulates that of the bacterial zinc transporter YiiP. These results provide a foundation for higher resolution structural studies and screening experiments to identify compounds that modulate ZnT8 activity.

Dataset Information

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.

Publications

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.

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