A comprehensive map of human glucokinase variant activity

Author:

Gersing Sarah,Cagiada Matteo,Gebbia Marinella,Gjesing Anette P.,Coté Atina G.,Seesankar Gireesh,Li Roujia,Tabet Daniel,Weile Jochen,Stein Amelie,Gloyn Anna L.,Hansen Torben,Roth Frederick P.,Lindorff-Larsen Kresten,Hartmann-Petersen RasmusORCID

Abstract

Abstract Background 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.

Funder

Novo Nordisk Fonden

Lundbeckfonden

Canadian Institutes of Health Research

Wellcome Trust

National Institute of Diabetes and Digestive and Kidney Diseases

Natur og Univers, Det Frie Forskningsråd

National Institutes of Health National Genome Research Institute

National Institutes of Health National Human Genome Research Institute

Royal Library, Copenhagen University Library

Publisher

Springer Science and Business Media LLC

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