A comprehensive map of human glucokinase variant activity
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A comprehensive map of human glucokinase variant activity. / 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, Rasmus.
In: Genome Biology, Vol. 24, No. 1, 97, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - A comprehensive map of human glucokinase variant activity
AU - Gersing, Sarah
AU - Cagiada, Matteo
AU - Gebbia, Marinella
AU - Gjesing, Anette P.
AU - Coté, Atina G.
AU - Seesankar, Gireesh
AU - Li, Roujia
AU - Tabet, Daniel
AU - Weile, Jochen
AU - Stein, Amelie
AU - Gloyn, Anna L.
AU - Hansen, Torben
AU - Roth, Frederick P.
AU - Lindorff-Larsen, Kresten
AU - Hartmann-Petersen, Rasmus
N1 - Publisher Copyright: © 2023, The Author(s).
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - Deep mutational scanning
KW - Diabetes
KW - Variants of uncertain significance
U2 - 10.1186/s13059-023-02935-8
DO - 10.1186/s13059-023-02935-8
M3 - Journal article
C2 - 37101203
AN - SCOPUS:85153917631
VL - 24
JO - Genome Biology (Online Edition)
JF - Genome Biology (Online Edition)
SN - 1474-7596
IS - 1
M1 - 97
ER -
ID: 346047556