Deep phenotyping was performed in three patients from two families carrying homozygous TYMP variants and presenting with lipoatrophic diabetes. The impact of the loss of TP expression was evaluated using a CRISPR-Cas9-mediated TP knockout (KO) strategy in human adipose stem cells (ASC), which can be differentiated into adipocytes in vitro. Protein expression profiles and cellular characteristics were investigated in this KO model.
All patients had TYMP loss-of-function variants and first presented with generalized loss of adipose tissue and insulin-resistant diabetes. CRISPR-Cas9-mediated TP KO in ASC abolished adipocyte differentiation and decreased insulin response, consistent with the patients\' phenotype. This KO also induced major oxidative stress, altered mitochondrial functions, and promoted cellular senescence. This translational study identifies a new role of TP by demonstrating its key regulatory functions in adipose tissue.
The implication of TP variants in atypical forms of monogenic diabetes shows that genetic diagnosis of lipodystrophic syndromes should include TYMP analysis. The fact that TP is crucial for adipocyte differentiation and function through the control of mitochondrial homeostasis highlights the importance of mitochondria in adipose tissue biology.
对来自两个家庭的三名患者进行了深度表型分析,这些患者携带纯合TYMP变体并表现为脂肪萎缩性糖尿病。在人脂肪干细胞(ASC)中使用CRISPR-Cas9介导的TP敲除(KO)策略评估了TP表达缺失的影响。可以在体外分化为脂肪细胞。在该KO模型中研究了蛋白质表达谱和细胞特征。
所有患者均有TYMP功能丧失变异,首先表现为全身脂肪组织丧失和胰岛素抵抗糖尿病。在ASC中CRISPR-Cas9介导的TPKO消除了脂肪细胞分化并降低了胰岛素反应,与患者表型一致。该KO还诱导了主要的氧化应激,改变了线粒体功能,促进细胞衰老。这项翻译研究通过证明其在脂肪组织中的关键调节功能,确定了TP的新作用。
TP变异在非典型形式的单基因糖尿病中的意义表明,脂肪营养不良综合征的遗传诊断应包括TYMP分析。TP通过控制线粒体稳态对脂肪细胞分化和功能至关重要这一事实突出了线粒体在脂肪组织生物学中的重要性。