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WFS1 encodes wolframin, an endoplasmic reticulum (ER) membrane glycoprotein initially implicated in recessive Wolfram syndrome. Subsequent association studies have evaluated common WFS1 variants for risk of Type 2 diabetes mellitus. WFS1 susceptibility alleles modulate pancreatic β-cell ER stress responses, Ca²⁺ homeostasis and insulin secretion, linking genetic variation in WFS1 to T2DM pathophysiology.
Family-based transmission disequilibrium testing in 152 parent-offspring trios identified overtransmission of the H611 allele and the R456-H611 haplotype to affected offspring (PMID:11916957), and subsequent case–control replication in 327 T2DM subjects versus 357 controls confirmed increased H611 allele frequency (OR 1.24, P = 0.02). Genome-wide and candidate‐gene meta-analyses in up to 14 139 patients and 16 109 controls further validated association of SNPs at WFS1 (e.g., rs10010131, rs752854; PMID:18040659), and two meta‐analyses of rs734312 and rs10010131 comprising 6 705–16 304 cases and 11 144–22 004 controls demonstrated protective G and A alleles respectively (P < 0.001) (PMID:23257691).
Common WFS1 risk alleles span missense and regulatory sites. Notably, c.1832G>A (p.Arg611His) maps to the luminal domain and correlates with reduced insulinogenic index and increased HOMA-IR in glucose‐tolerant and dysregulated individuals, supporting an additive effect on β-cell dysfunction (PMID:18568334). Loss-of‐function variants such as c.124C>T (p.Arg42Ter) are rare in T2DM populations but illustrate mechanistic parallels to heterozygous ER stress-inducing mutations (PMID:18040659).
Functional studies demonstrate that WFS1 deficiency intensifies ER stress and proapoptotic signaling in β-cells. Knock‐in and knockout models reveal N-glycosylated wolframin localizes to the ER where it maintains Ca²⁺ uptake rates via SERCA2b, and mutations such as R629W drastically shorten wolframin half-life leading to β-cell apoptosis (PMID:12913071; PMID:15994758; PMID:16806192). Disrupted WFS1–Smurf1 interactions also modulate wolframin ubiquitination and turnover under ER stress, linking variant‐specific degradation to altered UPR homeostasis (PMID:21454619).
Some population‐specific analyses report attenuated associations. A Japanese case–control study (n = 536/398) found nominal association of rs12511742 but lost significance after BMI adjustment (PMID:19258739), and T2DM polygenic risk scores did not predict PCOS in women, minimizing off‐target metabolic effects (PMID:22389004). These data underscore the need for ancestry‐diverse cohorts in risk estimation.
Collectively, genetic linkage, large‐scale association and functional concordance support a Strong clinical validity of WFS1 in T2DM susceptibility. While common variants yield modest effect sizes (OR 0.85–1.34), they cumulatively account for ~2–8.5% of T2DM trait variance and pinpoint ER stress as a critical β-cell vulnerability axis.
Key Take-home: WFS1 variants contribute to T2DM risk through ER stress–mediated β-cell dysfunction and represent a clinically actionable locus for refining diabetes risk stratification and therapeutic targeting.
Gene–Disease AssociationStrongMultiple large‐scale case–control and meta‐analysis studies in European and Asian populations (n>14 000 cases, >16 000 controls) and TDT in 152 trios Genetic EvidenceStrongOvertransmission in 152 trios and replicated association in >14 000 cases vs >16 000 controls ([PMID:11916957]; [PMID:18040659]) Functional EvidenceStrongER stress assays, knockout/knock-in models and degradation studies demonstrate wolframin’s role in β-cell ER Ca²⁺ homeostasis and cell survival ([PMID:12913071]; [PMID:15994758]) |