Introductory paragraph
Gene expression is tightly regulated with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function
1
. This silencing is largely controlled by non-coding elements and their disruption might cause human disease
2
. 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.
Initiated in 2000, the NHS‐funded genetic testing service for monogenic diabetes at the Exeter Genomics Laboratory, Royal Devon & Exeter Hospital, is the sole national provider for this service in England. The laboratory has undertaken testing for over 19,000 families and has diagnosed monogenic diabetes in over 9500 patients from the UK and across the world.Dr Kevin Colclough and colleagues here provide an insight into how genetic diagnostic testing leads to improved clinical care, how advances in testing technology are causing a paradigm shift in diagnosis, and how changes to test provision and funding are leading to the mainstreaming of genetic diagnosis in routine diabetes clinics.
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 mutations affecting a 42bp conserved region encompassed by a regulatory element in intron 2 of Hexokinase 1 (HK1), a pancreatic beta-cell disallowed gene. We demonstrated that these mutations resulted in expression of HK1 in the pancreatic beta-cells causing inappropriate insulin secretion and congenital hyperinsulinism. These mutations identify a regulatory region critical for cell-specific silencing. Importantly, this has revealed a new disease mechanism for non-coding mutations that cause inappropriate expression of a disallowed gene.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.