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Cited by 55Pancreatic function and diabetesGenomics and Rare DiseasesDiabetes and associated disorders

A comprehensive map of human glucokinase variant activity

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Gersing, Sarah, Cagiada, Matteo, Gebbia, Marinella, Gjesing, Anette P., Coté, Atina G., Seesankar, Gireesh, Li, Roujia, Tabet, Daniel +7 more·2023·Genome Biology
DOI 10.1186/s13059-023-02935-8PMC PMC10131484

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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.

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  • For GCK, the effects of nearly all possible missense and nonsense variants on enzyme activity and protein abundance have been studied in yeast complementation-based MAVEs.

    “examples of notable progress are seen for monogenic diabetes genes glucokinase (GCK), for which the effects of nearly all possible missense and nonsense variants on enzyme activity and protein abundance have been studied in yeast complementation-based MAVEs (114, 115)”

    From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [115]

    The Results section ('Assessing human GCK activity using yeast complementation'; page unavailable) reports yeast-complementation activity scores for 9003 of 9280 possible missense and nonsense GCK variants. The paper does not report corresponding measurements of protein abundance, so that part of the claim is unsupported by this source. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Gersing, S., Cagiada, M., Gebbia, M., Gjesing, A. P., Coté, A. G., Seesankar, G., Li, R., Tabet, D., Weile, J., Stein, A., Gloyn, A. L., Hansen, T., Roth, F. P., Lindorff-Larsen, K., & Hartmann-Petersen, R.
Affiliations
  • University of Copenhagen (DK)
  • University of Toronto (CA)
  • Stanford Medicine (US)
Corresponding author
Roth, Frederick P.
ORCID
Venue
Genome Biology
Publisher
Springer Science and Business Media LLC
Published
2023-04-26
Volume
24
Issue
1
Pages
97-97
ISSN
  • 1465-6906 (ISSN-L)
  • 1474-760X
DOI
10.1186/s13059-023-02935-8
PMC
PMC10131484
OpenAlex
W4367055489
Cited by
55
References
3
Citations by year
2026: 12 · 2025: 21 · 2024: 14 · 2023: 6 · 2022: 1 · 2012: 1
FWCI
13.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Genome biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Novo Nordisk Fonden (PRISM)
  • Lundbeckfonden (R272-2017-452, R209-2015-3283)
  • Canadian Institutes of Health Research (Foundation Grant)
  • Wellcome Trust (200837)
  • National Institute of Diabetes and Digestive and Kidney Diseases (U01-DK105535; U01-DK085545, UM1-DK126185)
  • Natur og Univers, Det Frie Forskningsråd (10.46540/2032-00007B)
  • National Institutes of Health National Genome Research Institute (Center of Excellence in Genomic Science Initiative (HG010461))
  • National Institutes of Health National Human Genome Research Institute (Impact of Genomic Variation on Function (IGVF) Initiative (HG011989))
  • Royal Library, Copenhagen University Library
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
glucokinase, GCK-MODY, hyperinsulinemic hypoglycemia, catalytic efficiency, protein conformational dynamics, active site, evolutionary conservation, genetic testing, insulin secretion
MeSH terms
Diabetes Mellitus, Type 2, Genetic Testing, Glucokinase, Humans, Mutation, Mutation, Missense

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