Further evidence that mutations in INScan be a rare cause of Maturity-Onset Diabetes of the Young (MODY)

Trine W Boesgaard,Charlotta Pisinger,Barbora Obermannova,Ehm A Andersson,Regine Bergholdt,Torben Hansen,Jeannet Lauenborg,Stepanka Pruhova,Flemming Pociot,Jan Lebl,Ondrej Cinek,Fabrizio Barbetti,Peter Damm,Oluf Pedersen

doi:10.1186/1471-2350-11-42

Abstract

BackgroundInsulin gene (INS) mutations have recently been described as a common cause of permanent neonatal diabetes (PNDM) and a rare cause of diabetes diagnosed in childhood or adulthood.MethodsINS was sequenced in 116 maturity-onset diabetes of the young (MODYX) patients (n = 48 Danish and n = 68 Czech), 83 patients with gestational diabetes mellitus (GDM), 34 type 1 diabetic patients screened negative for glutamic acid decarboxylase (GAD), and 96 glucose tolerant individuals. The control group was randomly selected from the population-based sampled Inter99 study.ResultsOne novel heterozygous mutation c.17G>A, R6H, was identified in the pre-proinsulin gene (INS) in a Danish MODYX family. The proband was diagnosed at 20 years of age with mild diabetes and treated with diet and oral hypoglycaemic agent. Two other family members who carried the INS R6H were diagnosed with diabetes when 51 years old and with GDM when 27 years old, respectively. A fourth mutation carrier had normal glucose tolerance when 20 years old. Two carriers of INS R6H were also examined twice with an oral glucose tolerance test (OGTT) with 5 years interval. They both had a ~30% reduction in beta-cell function measured as insulinogenic index. In a Czech MODYX family a previously described R46Q mutation was found. The proband was diagnosed at 13 years of age and had been treated with insulin since onset of diabetes. Her mother and grandmother were diagnosed at 14 and 35 years of age, respectively, and were treated with oral hypoglycaemic agents and/or insulin.ConclusionMutations in INS can be a rare cause of MODY and we conclude that screening for mutations in INS should be recommended in MODYX patients.

Highlights

Insulin gene (INS) mutations have recently been described as a common cause of permanent neonatal diabetes (PNDM) and a rare cause of diabetes diagnosed in childhood or adulthood [1,2,3,4]
We aimed to evaluate the prevalence and the diseaseassociated phenotype of INS mutations among diabetic patients diagnosed with Maturity-Onset Diabetes of the Young (MODY), anti-body negative type 1 diabetes (T1D) or gestational diabetes mellitus (GDM)
INS was sequenced in 116 unrelated MODYX probands: 48 Danish, age at diagnosis 24 ± 19 years, BMI 24.8 ± 5.5 kg/m2, and 68 Czech, age at diagnosis 18 ± 8 years, BMI 22.6 ± 5.0 kg/m2, 83 Danish diabetic patients previously diagnosed with GDM, age at examination 40 ± 7 years, BMI at examination 28.1 ± 6.5 kg/m2, 34 glutamic acid decarboxylase (GAD) autoantibody-negative T1D patients, age at diagnosis 20 ± 16 years and 96 glucose tolerant control individuals, age at examination 46 ± 7 years, BMI 26.4 ± 4.4 kg/m2

Summary

Introduction

Insulin gene (INS) mutations have recently been described as a common cause of permanent neonatal diabetes (PNDM) and a rare cause of diabetes diagnosed in childhood or adulthood [1,2,3,4]. MODY was initially clinically defined as autosomal dominantly inherited, non insulin dependent, early-onset diabetes, but there are at least eight distinct genetic subgroups of MODY, most of a recent screening for INS mutations in 252 patients diagnosed clinically with T1D between 6 months and 17 years of age identified 2 de novo heterozygous mutations G32S and R89C among the 25 (8%) antibody-negative patients [8]. GDM was defined as an abnormal glucose tolerance diagnosed for the first time in pregnancy

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