GCK gene mutations are a common cause of childhood-onset MODY (maturity-onset diabetes of the young) in Turkey.

Belma Haliloglu,Abdullah Bereket,Zeynep Atay,Tulay Guran,Saygın Abalı,Serap Turan,Sian Ellard,Gerald Hysenaj

doi:10.1111/cen.13121

Abstract

SummaryObjectiveInactivating heterozygous mutations in the GCK gene are a common cause of MODY and result in mild fasting hyperglycaemia, which does not require treatment. We aimed to identify the frequency, clinical and molecular features of GCK mutations in a Turkish paediatric cohort.Design and PatientsFifty‐four unrelated probands were selected based on the following criteria: age of diagnosis ≤17 years, family history of diabetes in at least two generations, anti‐GAD/ICA negative, BMI<95.p and follow‐up with diet, oral antidiabetic drug or low‐dose insulin treatment (≤0·5U/kg/d). A MODY probability score (www.diabetesgenes.org) was calculated and 21 patients with a score ≥75%, HbA1c levels ≤7·5% (58·5 mmol/mol) and fasting blood glucose (FBG) levels 99–145 mg/dl (5·5–8·0 mmol/l) were selected for Sanger sequencing of the GCK gene. Targeted next‐generation sequencing for all known monogenic diabetes genes was undertaken for any patient without a GCK gene mutation.Results GCK gene mutations (pathogenic or likely pathogenic variants) and a novel intronic variant of uncertain significance (c.208 + 3A>T) were identified in 13/54 probands (24%). Twelve of these patients had a MODY probability score ≥75%. FBG level and 2‐h glucose level in OGTT were 123 ± 14 mg/dl (6·8 ± 0·7 mmol/l) (107–157 mg/dl) and 181 ± 30 mg/dl (10·1 ± 1·6 mmol/l) (136–247 mg/dl), respectively. Average of glucose increment in OGTT was 58 ± 27 mg/dl (3·2 ± 1·5 mmol/l) (19–120 mg/dl), and mean HbA1c level was 6·5 ± 0·5% (47·5 ± 5·5 mmol/mol) (5·9–7·6%). Five novel missense mutations were identified (p.F123S, p.L58P, p.G246A, p.F419C, and p.S151C). Two patients treated with low‐dose insulin before the molecular analysis were able to stop treatment.ConclusionsApproximately 1 in 4 MODY cases in this Turkish paediatric cohort have a GCK mutation. Selection of patients for GCK gene analysis using the MODY probability score was an effective way of identifying most (11/12) patients with a GCK mutation.

Highlights

This enzyme is encoded by the GCK gene on chromosome 7p15Á3-p15Á1 comprising 12 exons and has three tissue-specific isoforms due to three different-sized exon 1.3 Inactivating heterozygous mutations in the GCK gene cause GCK-MODY that is characterized by asymptomatic, nonprogressive and mild fasting hyperglycaemia from birth.[2,4]
(26 males and 28 females) with a mean age at diagnosis of 8Á6 Æ 4Á2 years consented to participate in this study and fulfilled the inclusion criteria, which were the age of diagnosis ≤17 years, a minimum two-generation family history of diabetes, body mass index (BMI)
GCK sequencing was performed in 21 patients with a fasting blood glucose (FBG) level between 99 and 145 mg/dl (5Á5–8Á0 mmol/l), HbA1c levels ≤7Á5% (58Á5 mmol/mol) and MODY calculator scores ≥75% as calculated on www.diabetesgenes.org

Summary

Introduction

Glucokinase (GCK) is the enzyme which catalyses the first step of glycolysis and regulates insulin secretion as a glucose sensor.[1,2] This enzyme is encoded by the GCK gene on chromosome 7p15Á3-p15Á1 comprising 12 exons and has three tissue-specific isoforms due to three different-sized exon 1.3 Inactivating heterozygous mutations in the GCK gene cause GCK-MODY (maturity-onset diabetes of the young) that is characterized by asymptomatic, nonprogressive and mild fasting hyperglycaemia from birth.[2,4] Glucose increment in oral glucose tolerance test (OGTT) (0–120 min) is less than 54 mg/dl (3 mmol/l) in most cases.[5] HbA1c levels are just above the normal range and usually between 5Á6 and 7Á3% (37Á7–56Á3 mmol/mol) in these patients.[6] Microvascular and macrovascular complications are rare in patients with GCK mutations, and pharmacological treatment is rarely required.[4,7]. There are no publications that investigate the frequency of GCK mutations among MODY patients in the Turkish population. We aimed to determine the frequency of GCK mutations in a paediatric Turkish MODY cohort and to identify the molecular and clinical characteristics of GCK-MODY patients

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