Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability

Hum Mol Genet. 2014 Dec 15;23(24):6432-40. doi: 10.1093/hmg/ddu360.

Anne Raimondo ¹, Ali J Chakera ², Soren K Thomsen ¹, Kevin Colclough ³, Amy Barrett ¹, Elisa De Franco ⁴, Alisson Chatelas ¹, Huseyin Demirbilek ⁵, Teoman Akcay ⁶, Hussein Alawneh ⁷, International NDM Consortium, Sarah E Flanagan ⁴, Martijn Van De Bunt ¹, Andrew T Hattersley ², Anna L Gloyn ⁸, Sian Ellard ⁹, International NDM Consortium

Affiliations

1 Oxford Centre for Diabetes Endocrinology & Metabolism, University of Oxford, Oxford OX3 7LE, UK.
2 Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK, Macleod Diabetes and Endocrine Centre and.
3 Molecular Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK.
4 Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK.
5 Department of Paediatric Endocrinology, Diyarbakir Children State Hospital, Diyarbakir 21100, Turkey.
6 Division of Pediatric Endocrinology, Dr Sadi Konuk Education and Research Hospital, Bakirkoy, Istanbul 34147, Turkey.
7 Pediatric Endocrine Division, Queen Rania Al Abdullah Hospital for Children, King Hussein Medical Center, Royal Medical Services, Amman 11814, Jordan and.
8 Oxford Centre for Diabetes Endocrinology & Metabolism, University of Oxford, Oxford OX3 7LE, UK, Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LE, UK anna.gloyn@drl.ox.ac.uk.
9 Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK, Molecular Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK.

PMID: 25015100 DOI: 10.1093/hmg/ddu360

Abstract

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.

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