■HNF1A是控制胰腺β细胞分化的转录因子网络的重要组成部分,维护,和葡萄糖刺激的胰岛素分泌(GSIS)。HNF1A基因的变异导致了连续的蛋白质故障,从严重的功能丧失(LOF)变异导致高度渗透的年轻成熟型糖尿病(MODY)到较温和的LOF变异,其渗透程度要低得多,但在整个人群中患2型糖尿病的风险高达五倍。在将发现的变异分类和报告为与临床诊断相关之前,需要进行严格的审查。功能研究为将变体分类为致病性提供了实质性支持,或根据美国医学遗传学和基因组学学院(ACMG)和分子病理学协会(AMP)ACMG/AMP标准的其他建议进行变异解释。
■确定在印度单基因糖尿病患者中发现的HNF1A基因变异的分子基础。
■我们进行了功能性蛋白质分析,例如反式激活,蛋白质表达,DNA结合,核定位,和葡萄糖刺激的胰岛素分泌(GSIS)测定,同时对20名单基因糖尿病患者中发现的14种HNF1A变体进行结构预测分析。
■在14种变体中,4(28.6%)被解释为致病性,6(42.8%)可能致病,3(21.4%)作为不确定意义的变体,1(7.14%)为良性。具有致病性/可能的致病性变体的患者能够成功地从胰岛素转换为磺酰脲类(SU),从而使这些变体在临床上可行。
■我们的发现首次表明需要在分子表征过程中使用累加评分来进行精确医学中HNF1A变体的致病性评估。
HNF1A is an essential component of the transcription factor network that controls pancreatic β-cell differentiation, maintenance, and glucose stimulated insulin secretion (GSIS). A continuum of protein malfunction is caused by variations in the HNF1A gene, from severe loss-of-function (LOF) variants that cause the highly penetrant Maturity Onset Diabetes of the Young (MODY) to milder LOF variants that are far less penetrant but impart a population-wide risk of type 2 diabetes that is up to five times higher. Before classifying and reporting the discovered variations as relevant in clinical diagnosis, a critical review is required. Functional investigations offer substantial support for classifying a variant as pathogenic, or otherwise as advised by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) ACMG/AMP criteria for variant interpretation.
To determine the molecular basis for the variations in the HNF1A gene found in patients with monogenic diabetes in India.
We performed functional protein analyses such as transactivation, protein expression, DNA binding, nuclear localization, and glucose stimulated insulin secretion (GSIS) assay, along with structural prediction analysis for 14 HNF1A variants found in 20 patients with monogenic diabetes.
Of the 14 variants, 4 (28.6%) were interpreted as pathogenic, 6 (42.8%) as likely pathogenic, 3 (21.4%) as variants of uncertain significance, and 1 (7.14%) as benign. Patients harboring the pathogenic/likely pathogenic variants were able to successfully switch from insulin to sulfonylureas (SU) making these variants clinically actionable.
Our findings are the first to show the need of using additive scores during molecular characterization for accurate pathogenicity evaluations of HNF1A variants in precision medicine.