A comprehensive map of human glucokinase variant activity
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Glucokinase (GCK) regulates insulin secretion to maintain appropriate blood glucose levels. Sequence variants can alter GCK activity to cause hyperinsulinemic hypoglycemia or hyperglycemia associated with GCK-maturity-onset diabetes of the young (GCK-MODY), collectively affecting up to 10 million people worldwide. Patients with GCK-MODY are frequently misdiagnosed and treated unnecessarily. Genetic testing can prevent this but is hampered by the challenge of interpreting novel missense variants.
Result
Here, we exploit a multiplexed yeast complementation assay to measure both hyper- and hypoactive GCK variation, capturing 97% of all possible missense and nonsense variants. Activity scores correlate with in vitro catalytic efficiency, fasting glucose levels in carriers of GCK variants and with evolutionary conservation. Hypoactive variants are concentrated at buried positions, near the active site, and at a region of known importance for GCK conformational dynamics. Some hyperactive variants shift the conformational equilibrium towards the active state through a relative destabilization of the inactive conformation.
Conclusion
Our comprehensive assessment of GCK variant activity promises to facilitate variant interpretation and diagnosis, expand our mechanistic understanding of hyperactive variants, and inform development of therapeutics targeting GCK.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 97 |
| Tidsskrift | Genome Biology |
| Vol/bind | 24 |
| Udgave nummer | 1 |
| Antal sider | 23 |
| ISSN | 1474-7596 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
Open access funding provided by Royal Danish Library. This work funded by the Novo Nordisk Foundation ( https://novonordiskfonden.dk ) challenge program PRISM (to K.L.-L., A.S. & R.H.-P.), the Lundbeck Foundation ( https://www.lundbeckfonden.com ) R272-2017–452 and R209-2015–3283 (to A.S.), and Danish Council for Independent Research (Det Frie Forskningsråd) (https://dff.dk) 10.46540/2032-00007B (to R.H.P.). F.R. acknowledges support from the National Institutes of Health National Human Genome Research Institute (NIH/NHGRI) Center of Excellence in Genomic Science Initiative (HG010461), the NIH/NHGRI Impact of Genomic Variation on Function (IGVF) Initiative (HG011989), and from a Canadian Institutes of Health Research Foundation Grant. A.L.G. is a Wellcome Senior Fellow in Basic Biomedical Science. A.L.G. is funded by the Wellcome (200837) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (U01-DK105535; U01-DK085545, UM1-DK126185). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funding Information:
The authors thank Sofie V. Nielsen for helpful conversation on experimental procedures, and Amal Al-Chaer for assistance with the Bioanalyzer system and Illumina sequencing. We acknowledge the use of computing resources at the core facility for biocomputing at the Department of Biology, University of Copenhagen. The review history is available as Additional file 3. Anahita Bishop was the primary editor of this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Publisher Copyright:
© 2023, The Author(s).
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