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A Review of Functional Characterization of Single Amino Acid Change Mutations in HNF Transcription Factors in MODY Pathogenesis
The Protein Journal ( IF 1.9 ) Pub Date : 2021-05-05 , DOI: 10.1007/s10930-021-09991-8
Hasan Çubuk 1 , Özlem Yalçın Çapan 1
Affiliation  

Mutations in HNF transcription factor genes cause the most common subtypes of maturity-onset of diabetes of youth (MODY), a monogenic form of diabetes mellitus. Mutations in the HNF1-α, HNF4-α, and HNF1-β genes are primarily considered as the cause of MODY3, MODY1, and MODY5 subtypes, respectively. Although patients with different subtypes display similar symptoms, they may develop distinct diabetes-related complications and require different treatments depending on the type of the mutation. Genetic analysis of MODY patients revealed more than 400 missense/nonsense mutations in HNF1-α, HNF4-α, and HNF1-β genes, however only a small portion of them are functionally characterized. Evaluation of nonsense mutations are more direct as they lead to premature stop codons and mostly in mRNA decay or nonfunctional truncated proteins. However, interpretation of the single amino acid change (missense) mutation is not such definite, as effect of the variant may vary depending on the location and also the substituted amino acid. Mutations with benign effect on the protein function may not be the pathologic variant and further genetic testing may be required. Here, we discuss the functional characterization analysis of single amino acid change mutations identified in HNF1-α, HNF4-α, and HNF1-β genes and evaluate their roles in MODY pathogenesis. This review will contribute to comprehend HNF nuclear family-related molecular mechanisms and to develop more accurate diagnosis and treatment based on correct evaluation of pathologic effects of the variants.



中文翻译:

MODY 发病机制中 HNF 转录因子中单个氨基酸变化突变的功能表征综述

HNF 转录因子基因的突变导致最常见的成年型青年糖尿病 (MODY) 亚型,这是一种单基因形式的糖尿病。在突变HNF1-αHNF4-α,和HNF1-β的基因主要是分别视为MODY3,MODY1的原因,和MODY5亚型。尽管不同亚型的患者表现出相似的症状,但他们可能会出现不同的糖尿病相关并发症,并且根据突变的类型需要不同的治疗。MODY 患者的基因分析显示HNF1-αHNF4-αHNF1-β 中有超过 400 个错义/无义突变基因,然而只有一小部分具有功能特征。对无义突变的评估更为直接,因为它们会导致过早的终止密码子,并且主要是在 mRNA 衰变或无功能的截短蛋白中。然而,对单一氨基酸变化(错义)突变的解释并不是那么明确,因为变异的影响可能会因位置和取代的氨基酸而异。对蛋白质功能有良性影响的突变可能不是病理变异,可能需要进一步的基因检测。在这里,我们讨论了在HNF1-αHNF4-αHNF1-β 中鉴定的单个氨基酸变化突变的功能表征分析基因并评估它们在 MODY 发病机制中的作用。本综述将有助于理解 HNF 核家族相关的分子机制,并在正确评估变异的病理影响的基础上开发更准确的诊断和治疗。

更新日期:2021-05-05
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