Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability.
De Franco, E
International NDM Consortium
Van De Bunt, M
International NDM Consortium
Human Molecular Genetics
Oxford University Press (OUP): Policy B - Oxford Open Option B
This is the final version of the article. Available from Oxford University Press via the DOI in this record.
Mutations in glucokinase (GCK) cause a spectrum of glycemic disorders. Heterozygous loss-of-function mutations cause mild fasting hyperglycemia irrespective of mutation severity due to compensation from the unaffected allele. Conversely, homozygous loss-of-function mutations cause permanent neonatal diabetes requiring lifelong insulin treatment. This study aimed to determine the relationship between in vitro mutation severity and clinical phenotype in a large international case series of patients with homozygous GCK mutations. Clinical characteristics for 30 patients with diabetes due to homozygous GCK mutations (19 unique mutations, including 16 missense) were compiled and assigned a clinical severity grade (CSG) based on birth weight and age at diagnosis. The majority (28 of 30) of subjects were diagnosed before 9 months, with the remaining two at 9 and 15 years. These are the first two cases of a homozygous GCK mutation diagnosed outside infancy. Recombinant mutant GCK proteins were analyzed for kinetic and thermostability characteristics and assigned a relative activity index (RAI) or relative stability index (RSI) value. Six of 16 missense mutations exhibited severe kinetic defects (RAI ≤ 0.01). There was no correlation between CSG and RAI (r(2) = 0.05, P = 0.39), indicating that kinetics alone did not explain the phenotype. Eighty percent of the remaining mutations showed reduced thermostability, the exceptions being the two later-onset mutations which exhibited increased thermostability. Comparison of CSG with RSI detected a highly significant correlation (r(2) = 0.74, P = 0.002). We report the largest case series of homozygous GCK mutations to date and demonstrate that they can cause childhood-onset diabetes, with protein instability being the major determinant of mutation severity.
This work was supported by the Wellcome Trust (grant number 095101/Z/10/Z to A.L.G.). A.L.G. is a Wellcome Trust Senior Fellow in Basic and Biomedical Science. A.T.H. and S.E. are Wellcome Trust Senior Investigators. A.T.H. is a National Institute for Health Research (NIHR) Senior Investigator. A.T.H. is funded by the NIHR Exeter Clinical Research Facility. This article presents independent research supported by the NIHR Exeter Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Vol. 23, No. 24, pp. 6432 - 6440
Place of publication