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 (r2 = 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 (r2 = 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.
Highlights
Homozygous mutations in the gene encoding the enzyme glucokinase (GCK) cause a rare form of permanent neonatal diabetes (PNDM; OMIM entry #606176) that requires lifelong insulin treatment
We report a series of 30 patients with 19 unique homozygous GCK mutations, including the first two cases of a homozygous mutation diagnosed with diabetes outside infancy
This study significantly extends the phenotypic spectrum of naturally occurring homozygous GCK mutations, and utilizes both clinical and in vitro approaches to provide the first systematic investigation of genotype – phenotype correlations within a large group of patients with homozygous GCK mutations
Summary
Homozygous mutations in the gene encoding the enzyme glucokinase (GCK) cause a rare form of permanent neonatal diabetes (PNDM; OMIM entry #606176) that requires lifelong insulin treatment. Heterozygous inactivating GCK mutations are less deleterious and manifest in a mild fasting hyperglycemia from birth (5.5 – 8 mmol l21) otherwise known as maturity-onset diabetes of the young; subtype GCK (GCK-MODY; OMIM entry #125851) [8]. Pharmacological treatment for these individuals is not usually required [9]
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