Glucokinase Gene Mutation Screening in Argentinean Clinically Characterized MODY Patients

Abstract

Introduction: Mutations in the glucokinase gene (GCK) produce a subtype of Maturity onset diabetes in the young (MODY), named MODY 2. To date over than 190 different mutations have been identified, distributed over the coding regions and the exon–intron boundaries of the gene. The aim of this work was to study the nature and frequency of mutations in the GCK gene, in a MODY clinically characterized Argentinean population.

Material and Methods: Seventy unrelated individuals were selected based on MODY clinical features. The study methodology consisted in PCR amplification of the coding regions of the GCK gene, SSCP electrophoresis analysis of the amplified fragments and direct sequencing of the fragments with abnormal electrophoresis pattern.

Results: We identified a total of six patients with mutations in the GCK gene. This included two novel mutations: g.1831C>A, g.3792T>A, one already reported by our group, g.168fsdelC (same mutation in two non-related patients) and two already reported: p.Gln138Pro and p.Gly261Glu. With that data, we could establish the prevalence of MODY 2 among the patients in study reaching to 8.6%.

Discussion: The main contribution of this study is to inform about two novel mutations not described to date and to make an approach to the establishment of the prevalence of MODY 2 in the population under study. These findings contribute to confirm the allelic heterogeneity of GCK gene mutations and may provide an insight into the structure-function relationship of the GCK.

Key words

diabetes - glucokinase - MODY 2 - mutation

References

• 1 Barrio R, Bellanné-Chantelot C, Moreno JC. et al . Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families.  J Clin Endocrinol Metab. 2002;  87 ((6)) 2532-2539
• 2 Beards F, Frayling T, Bulman M. et al . Mutations in hepatocyte nuclear factor 4α are not a common cause of maturity-onset diabetes of the young in the UK.  Diabetes. 1998;  47 1152-1154
• 3 Chankiewitz E, Peschke D, Herberg L. et al . Did the gradual loss of GLUT2 cause a shift to diabetic disorders in the New Zealand obese mouse (NZO/Hl)?.  Exp Clin Endocrinol Diabetes; 05. 2006;  114 ((5)) 262-269
• 4 Chèvre JC, Hani EH, Boutin P. et al . Mutation screening in 18 Caucasian families suggest the existence of other MODY genes.  Diabetologia. 1998;  41 ((9)) 1017-1023
• 5 Dimitriadis G, Boutati E, Raptis SA. The importance of adipose tissue in diabetes pathophysiology and treatment.  Horm Metab Res. 2007;  39 ((10)) 705-706
• 6 Doria A, Plengvidhya N. Recent advances in the genetics of maturity onset diabetes in the young and other forms of autosomal dominant diabetes.  Curr Opinion Endocrinol Diabetes. 2000;  7 203-210
• 7 Ellard S, Beards F, Allen LI. et al . A high prevalence of glucokinase mutations in gestational diabetic subjects selected by clinical criteria.  Diabetologia. 2000;  43 ((2)) 250-253
• 8 Ellard S, Bellanné-Chantelot C, Hattersley AT. Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. European Molecular Genetics Quality Network (EMQN) MODY group.  Diabetologia. 2008;  51 546-553
• 9 Fajans SS, Bell GI, Polonsky KS. Molecular mechanism and clinical pathophysiology of maturity-onset diabetes of the young.  N Engl J Med. 2001;  345 971-980
• 10 Frechtel GD, López AP, Rodríguez M. et al . A novel mutation in Exon 5 of the Glucokinase gene in an Argentine MODY Family.  Molecular Diagnosis. 2003;  7 ((2)) 129-131
• 11 Froguel P, Vaxillaire M, Sun F. et al . Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus.  Nature. 1992;  356 ((6365)) 162-164
• 12 Froguel P, Zouali H, Vionnet N. et al . Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus.  N Engl J Med. 1993;  328 697-702
• 13 García-Herrero CM, Galán M, Vincent O. et al . Functional analysis of human glucokinase gene mutations causing MODY 2: exploring the regulatory mechanisms of glucokinase activity.  Diabetología. 2007;  50 ((2)) 325-333
• 14 Haines L MSC, Kay Chong Wan DPHIL, Lynn R. et al . Rising incidence of type 2 diabetes in children in the UK.  Diabetes Care. 2007;  30 1097-1101
• 15 Hara M, Shen J, Pugh W. et al . Sustained expression of hepatocyte nuclear factor-6 leads to loss of pancreatic beta-cells by apoptosis.  Exp Clin Endocrinol Diabetes. 2007;  115 ((10)) 654-661
• 16 Hummel M, Vasseur F, Mathieu C. et al . Two Caucasian families with the hepatocyte nuclear factor-1Alpha mutation Tyr218Cys.  Exp Clin Endocrinol Diabetes. 2007;  115 ((1)) 62-64
• 17 Lindner TH, Cockburn BN, Bell GI. Molecular Genetics of MODY in Germany.  Diabetologia. 1999;  42 121-123
• 18 Mahalingam B, Cuesta Muñoz A, Davis EA. et al . Structural model of human glucokinase in complex with glucose and ATP.  Diabetes. 1999;  48 1698-1999
• 19 Mantovani V, Salardi S, Cerreta V. et al . Identification of eight novel glucokinase mutations in Italian children with maturity-onset diabetes of the young.  Hum Mutat. 2003;  22 ((4)) 338
• 20 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus . Diabetes Care. 1997;  20 1 , [10]
• 21 Rosenbloom AL. Emerging epidemic of type 2 diabetes in Mexican-American youth.  Diabetes Care. 1999;  22 345-354
• 22 Stoffel M, Froguel PH, Takeda J. et al . Human glucokinase gene: Isolation, characterization and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus.  Proc Natl Acad Sci USA Genetics. 1992;  89 7698-7702
• 23 Tanizawa Y, Matsutani A, Chiu KC. et al . Human glucokinase gene: isolation, structural characterization and identification of a microsatellite repeat polymorphism.  Mol Endocrinol. 1992;  6 1070-1081
• 24 The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. . Committee report.  Diabetes Care. 2000;  23 ((Suppl. 1)) [11]
• 25 Thomson KL, Gloyn AL, Colclough K. et al . Identification of 21 novel glucokinase (GCK) mutations in UK and European Caucassians with Maturity Onset Diabetes of the Young (MODY).  Hum Mutat Nov. 2003;  22 ((5)) 417
• 26 Tsakiris D, Ioannou K. An underdiagnosed type of diabetes: The MODY syndromes. Pathophysiology, clinical presentation and renal disease progression.  J Nephrol. 2004;  7 637-641
• 27 Velho G, Petersen KF, Perseghin G. et al . Impaired hepatic glycogen synthesis in glucokinase-deficient (MODY-2) subjects.  J Clin Invest. 1996;  98 ((8)) 1755-1761
• 28 Velho G, Blanche H, Vaxillaire M. et al . Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY 2 families.  Diabetologia. 1997;  40 217-224
• 29 Velho G, Froguel P. Genetic, metabolic and clinical characteristics of maturity onset diabetes of the young.  Eur J Endocrinol. 1998;  138 233-239
• 30 Winckler W, Weedon MN, Graham RR. et al . Evaluation of common variants in the six known maturity-onset diabetes of the young (MODY) genes for association with type 2 diabetes.  Diabetes. 2007;  56 ((3)) 685-693

Correspondence