Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Novo Nordisk Research Center Indianapolis, Indianapolis, IN, United States.
Front Endocrinol (Lausanne). 2022 Jun 29;13:891586. doi: 10.3389/fendo.2022.891586. eCollection 2022.
The intestinal hormone, glucose-dependent insulinotropic polypeptide (GIP), is involved in important physiological functions, including postprandial blood glucose homeostasis, bone remodeling, and lipid metabolism. While mutations leading to physiological changes can be identified in large-scale sequencing, no systematic investigation of GIP missense variants has been performed. Here, we identified 168 naturally occurring missense variants in the human GIP genes from three independent cohorts comprising ~720,000 individuals. We examined amino acid changing variants scattered across the pre-pro-GIP peptide using effect predictions, which revealed that the sequence of the fully processed GIP hormone is more protected against mutations than the rest of the precursor protein. Thus, we observed a highly species-orthologous and population-specific conservation of the GIP peptide sequence, suggestive of evolutionary constraints to preserve the GIP peptide sequence. Elucidating the mutational landscape of GIP variants and how they affect the structural and functional architecture of GIP can aid future biological characterization and clinical translation.
肠激素葡萄糖依赖性胰岛素释放肽（GIP）参与许多重要的生理功能，包括餐后血糖稳态、骨重塑和脂代谢。虽然在大规模测序中可以识别导致生理变化的突变，但尚未对 GIP 错义变异进行系统研究。在这里，我们从三个独立的队列中鉴定了人类 GIP 基因中的 168 种天然存在的错义变异，这些队列包含约 72 万人。我们使用效应预测检查了分散在 pre-pro-GIP 肽中的氨基酸变化变体，结果表明，完全加工的 GIP 激素序列比前体蛋白的其余部分更能抵抗突变。因此，我们观察到 GIP 肽序列在高度物种同源和人群特异性上的保守性，这表明进化的约束作用是为了保持 GIP 肽序列。阐明 GIP 变体的突变景观以及它们如何影响 GIP 的结构和功能架构，可以帮助未来的生物学特征和临床转化。
