Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism.
Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism.
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DOI：
10.1038/s41588-022-01204-x
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发表时间：
2022-11
期刊：
影响因子：
30.8
通讯作者：
Flanagan SE
中科院分区：
文献类型：
--
作者：
Wakeling MN;Owens NDL;Hopkinson JR;Johnson MB;Houghton JAL;Dastamani A;Flaxman CS;Wyatt RC;Hewat TI;Hopkins JJ;Laver TW;van Heugten R;Weedon MN;De Franco E;Patel KA;Ellard S;Morgan NG;Cheesman E;Banerjee I;Hattersley AT;Dunne MJ;International Congenital Hyperinsulinism Consortium;Richardson SJ;Flanagan SE
基因表达受到严格调控，当其蛋白产物破坏正常细胞功能时，许多基因表现出细胞特异性沉默。这种沉默在很大程度上是由非编码元件控制的，它们的破坏可能导致人类疾病。我们对非编码区进行了基因不可知筛选，以发现先天性高胰岛素血症的新分子原因。研究发现了14个非编码的新变异，这些变异影响了己糖激酶1 （HK1）内含子2中一个调控元件所包含的42bp的保守区域。HK1在除肝脏和胰腺细胞外的所有组织中广泛表达，因此在这些特定组织中被称为“不允许的基因”。我们证明，这些变异导致胰腺β细胞中HK1的抑制丧失，从而导致胰岛素分泌和先天性高胰岛素症。利用从公共存储库获取的表观基因组数据，我们证明了这些变异位于一个调控区域内，我们确定该区域对细胞特异性沉默至关重要。重要的是，这揭示了导致不被允许的基因不适当表达的非编码变异的疾病机制。
Gene expression is tightly regulated with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function. This silencing is largely controlled by non-coding elements and their disruption might cause human disease. We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo variants affecting a 42bp conserved region encompassed by a regulatory element in intron 2 of Hexokinase 1 (HK1). HK1 is widely expressed across all tissues except for liver and pancreatic beta-cells and is thus termed a “disallowed gene” in these specific tissues. We demonstrated that the variants result in a loss of repression of HK1 in pancreatic beta-cells, thereby causing insulin secretion and congenital hyperinsulinism. Using epigenomic data accessed from public repositories, we demonstrated that these variants reside within a regulatory region that we determine to be critical for cell-specific silencing. Importantly, this has revealed a disease mechanism for non-coding variants that cause inappropriate expression of a disallowed gene.
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