作者
Matthew Wakeling,Nick D.L. Owens,Jessica R. Hopkinson,Matthew B. Johnson,Jayne A. L. Houghton,Antonia Dastamani,Christine S. Flaxman,Rebecca C. Wyatt,Thomas I Hewat,Jasmin J. Hopkins,Thomas W Laver,Rachel van Heugten,Michael N. Weedon,Elisa De Franco,Kashyap A. Patel,Sian Ellard,Noel G. Morgan,Edmund Cheesman,Indraneel Banerjee,Andrew T. Hattersley,Mark J. Dunne,Ivo Barić,Liat de Vries,Samar S. Hassan,Khadija Nuzhat Humayun,Floris Levy-Khademi,Catarina Limbert,Birgit Rami-Merhar,Verónica Mericq,Kristen Neville,Yasmine Ouarezki,Ana Tangari,Charles Verge,Esko Wiltshire,Sarah J. Richardson,Sarah E. Flanagan
摘要
Gene expression is tightly regulated, with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function1. This silencing is largely controlled by non-coding elements, and their disruption might cause human disease2. 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 42-bp conserved region encompassed by a regulatory element in intron 2 of the hexokinase 1 gene (HK1). HK1 is widely expressed across all tissues except in the 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.