Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
BMC Genet. 2013 Apr 23;14:28. doi: 10.1186/1471-2156-14-28.
The discovery of TCF7L2 as a global type 2 diabetes (T2D) gene has sparked investigations to explore the clinical utility of its variants for guiding the development of new diagnostic and therapeutic strategies. However, interpreting the resulting associations into function still remains unclear. Canonical Wnt signaling regulates β-catenin and its binding with TCF7L2, which in turn is critical for the production of glucagon-like peptide-1 (GLP-1). This study examines the role of a novel frame-shift insertion discovered in a conserved region of WNT16a, and it is proposed that this mutation affects T2D susceptibility in conjunction with gene variants in TCF7L2.
Our results predicted that the insertion would convert the upstream open reading frame in the Wnt16a mRNA to an alternative, in-frame translation initiation site, resulting in the prevention of nonsense-mediated decay, leading to a consequent stabilization of the mutated WNT16a message. To examine the role of Wnt16a in the Wnt signaling pathway, DNA and serum samples from 2,034 individuals (48% with T2D) from the Sikh Diabetes Study were used in this investigation. Prevalence of Wnt16a insertion did not differ among T2D cases (33%) and controls (32%). However, there was a 3.2 fold increase in Wnt16a mRNA levels in pancreatic tissues from the insertion carriers and a significant increase (70%, p < 0.0001) in luciferase activity in the constructs carrying the insertion. The expression of TCF7L2 mRNA in pancreas was also elevated (~23-fold) among the insertion carriers (p=0.003).
Our results suggest synergistic effects of WNT16a insertion and the at-risk 'T' allele of TCF7L2 (rs7903146) for elevating the expression of TCF7L2 in human pancreas which may affect the regulation of downstream target genes involved in the development of T2D through Wnt/β-catenin/TCF7L2 signaling pathway. However, further studies would be needed to mechanistically link the two definitively.
TCF7L2 作为一种 2 型糖尿病（T2D）的全基因组基因被发现后，人们开始探索其变异体在指导新的诊断和治疗策略方面的临床应用。然而，将这些关联解释为功能仍然不清楚。经典的 Wnt 信号通路调节 β-连环蛋白及其与 TCF7L2 的结合，这对胰高血糖素样肽-1（GLP-1）的产生至关重要。本研究检测了在 WNT16a 保守区域发现的一种新型框移插入的作用，该突变与 TCF7L2 中的基因变异一起影响 T2D 的易感性。
我们的结果预测，该插入将导致 Wnt16a mRNA 的上游开放阅读框转换为一个替代的、框架内的翻译起始位点，从而防止无意义介导的衰变，导致突变的 Wnt16a 消息的稳定。为了研究 Wnt16a 在 Wnt 信号通路中的作用，本研究使用了来自锡克糖尿病研究的 2034 名个体（48%为 T2D）的 DNA 和血清样本。在 T2D 病例（33%）和对照组（32%）中，Wnt16a 插入的发生率没有差异。然而，在插入携带者的胰腺组织中，Wnt16a mRNA 水平增加了 3.2 倍，携带插入的构建体中的荧光素酶活性显著增加（70%，p < 0.0001）。在插入携带者中，TCF7L2 mRNA 的表达也升高（~23 倍）（p=0.003）。
我们的结果表明，WNT16a 插入和 TCF7L2 易感性“T”等位基因（rs7903146）之间存在协同作用，可提高人类胰腺中 TCF7L2 的表达，这可能通过 Wnt/β-连环蛋白/TCF7L2 信号通路影响参与 T2D 发生的下游靶基因的调节。然而，需要进一步的研究来明确它们之间的关系。
