A comprehensive map of human glucokinase variant activity.

Autor:	Gersing S; The Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark., Cagiada M; The Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark., Gebbia M; Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, M5G 1X5, Canada., Gjesing AP; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Coté AG; Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, M5G 1X5, Canada., Seesankar G; Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, M5G 1X5, Canada., Li R; Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, M5G 1X5, Canada.; Department of Computer Science, University of Toronto, Toronto, ON, M5T 3A1, Canada., Tabet D; Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, M5G 1X5, Canada.; Department of Computer Science, University of Toronto, Toronto, ON, M5T 3A1, Canada., Weile J; Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, M5G 1X5, Canada.; Department of Computer Science, University of Toronto, Toronto, ON, M5T 3A1, Canada., Stein A; The Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark., Gloyn AL; Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA., Hansen T; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Roth FP; Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada. fritz.roth@utoronto.ca.; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada. fritz.roth@utoronto.ca.; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, M5G 1X5, Canada. fritz.roth@utoronto.ca.; Department of Computer Science, University of Toronto, Toronto, ON, M5T 3A1, Canada. fritz.roth@utoronto.ca., Lindorff-Larsen K; The Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark. lindorff@bio.ku.dk., Hartmann-Petersen R; The Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark. rhpetersen@bio.ku.dk.
Jazyk:	angličtina
Zdroj:	Genome biology [Genome Biol] 2023 Apr 26; Vol. 24 (1), pp. 97. Date of Electronic Publication: 2023 Apr 26.
DOI:	10.1186/s13059-023-02935-8
Abstrakt:	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. (© 2023. The Author(s).)
Databáze:	MEDLINE
Externí odkaz:	Full text from SpringerLink