Publisher correction: Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes (vol 9, 321, 2018)

Correction to: Nature Communications https://doi.org/10.1038/s41467-017-02380-9 , published online 22 January 2018 In the originally published version of this Article, the af fi liation details for Santi González, Jian ’ an Luan and Claudia Langenberg were inadvertently omitted. Santi González should have been af fi liated with 'Barcelona Supercomputing Center (BSC), Joint BSC-CRG-IRB Research Program in Computational Biology, 08034 Barcelona, Spain ’ , and Jian ’ an Luan and Claudia Langenberg should have been af fi liated with ‘ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK ’ . Furthermore, the abstract contained an error in the SNP ID for the rare variant in chromosome Xq23, which was incorrectly given as rs146662057 and should have been rs146662075. These errors have now been corrected in both the PDF and HTML versions of the Article

Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes

The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662075, associated with a twofold increased risk for T2D in males. rs146662075 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches

L amino acid transporter structure and molecular bases for the asymmetry of substrate interaction

L-amino acid transporters (LATs) play key roles in human physiology and are implicated in several human pathologies. LATs are asymmetric amino acid exchangers where the low apparent affinity cytoplasmic side controls the exchange of substrates with high apparent affinity on the extracellular side. Here, we report the crystal structures of an LAT, the bacterial alanine-serine-cysteine exchanger (BasC), in a non-occluded inward-facing conformation in both apo and substrate-bound states. We crystallized BasC in complex with a nanobody, which blocks the transporter from the intracellular side, thus unveiling the sidedness of the substrate interaction of BasC. Two conserved residues in human LATs, Tyr 236 and Lys 154, are located in equivalent positions to the Na1 and Na2 sites of sodium-dependent APC superfamily transporters. Functional studies and molecular dynamics (MD) calculations reveal that these residues are key for the asymmetric substrate interaction of BasC and in the homologous human transporter Asc-1.This work was funded by the Spanish Ministry of Science and Innovation (grant SAF2015-64869-R-FEDER), the Fundació la Marató TV3 (20132330), Research Contract with SIDRA Medicine (Qatar), CIBERER ACCI 2017-U731, and the Generalitat de Catalunya (grant SGR2009-1355)

A loss-of-function splice acceptor variant in IGF2 is protective for type 2 diabetes

Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the IGF2 gene associated with ∼20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between IGF2 exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage–dependent reduction in the expression of IGF2 isoform 2. In individuals who do not carry the protective allele, expression of IGF2 isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in IGF2 isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing IGF2 isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction