Short Communication MODY 2: Mutation identification and molecular ancestry in a Brazilian family Adolfo J. Mota a, ⁎, Simone Brüggemann b , Fabrício F. Costa c, d, ⁎⁎ a Departamento de Biociências e Diagnóstico Oral, Faculdade de Odontologia de São José dos Campos, Universidade Estadual Paulista “Júlio de Mesquita Filho” (UNESP), São José dos Campos, SP, Brazil b Prefeitura Municipal de Sao Jose dos Campos (PMSJC), Sao Jose dos Campos, SP, Brazil c Cancer Biology and Epigenomics Program, Children's Hospital of Chicago Research Center and Department of Pediatrics, Northwestern University's Feinberg School of Medicine, Chicago, IL 60614, USA d Datagenno Interactive Research Ltda, Rua Gastão Machado 66, Edifício CME, Salas 503/504, Campos dos Goytacazes, Rio de Janeiro, RJ 28035-120, Brazil abstract article info Article history: Accepted 10 October 2012 Available online 23 October 2012 Keywords: MODY2 Glucokinase (GCK) New mutations Brazilian family Maturity Onset Diabetes of the Young (MODY) is a heterogeneous group of genetic diseases characterized by a primary defect in insulin secretion and hyperglycemia, non-ketotic disease, monogenic autosomal domi- nant mode of inheritance, age at onset less than 25 years, and lack of auto-antibodies. It accounts for 2–5% of all cases of non-type 1 diabetes. MODY subtype 2 is caused by mutations in the glucokinase (GCK) gene. In this study, we sequenced the GCK gene of two volunteers with clinical diagnosis for MODY2 and we were able to identify four mutations including one for a premature stop codon (c.76C>T). Based on these re- sults, we have developed a specific PCR-RFLP assay to detect this mutation and tested 122 related volunteers from the same family. This mutation in the GCK gene was detected in 21 additional subjects who also had the clinical features of this genetic disease. In conclusion, we identified new GCK gene mutations in a Brazilian family of Italian descendance, with one due to a premature stop codon located in the second exon of the gene. We also developed a specific assay that is fast, cheap and reliable to detect this mutation. Finally, we built a molecular ancestry model based on our results for the migration of individuals carrying this genetic mutation from Northern Italy to Brazil. © 2012 Elsevier B.V. All rights reserved. 1. Introduction Maturity Onset Diabetes of the Young (MODY; OMIM# 606391) is an autosomal dominant genetic disease characterized by an inherited form of non-ketotic diabetes. The symptoms usually develop in child- hood, adolescence or young adulthood. MODY is a heterogeneous dis- ease regarding the genetic and clinical features, can affect individuals worldwide and was described in all geographic locations and ethnic groups (Fajans et al., 2001). There are 11 types of MODY described so far and each has a differ- ent group of genes involved in the clinical manifestations of the dis- ease. At least seven genes have been associated with this genetic disorder such as the glucokinase (GCK), hepatocyte nuclear factor-1-alpha (HNF1A), pancreas/duodenum homeobox protein-1 (PDX1), among others. The type 2 (MODY2) is defined as a familial form of non-insulin- dependent diabetes mellitus (NIDDM), characterized by early onset with an autosomal dominant inheritance pattern exhibiting a mild fasting hyperglycemia (Fajans et al., 2001). It is caused by mutations in the gluco- kinase (GCK) gene, which encodes the first enzyme of the glycolytic path- way. The GCK gene is mapped to human chromosome 7p15.3–p15.1 and consists of 10 exons that span approximately 45.169 bp encoding a 465-amino-acid protein. There are three tissue-specific isoforms due to an alternative splicing at exon 1 (Tinto et al., 2008). GCK acts as a glucose sensor in the pancreas and liver, and presents a peculiar sigmoidal glucose saturation curve, which indicates cooperative behavior. Since the first correlation between the glucokinase locus on chro- mosome 7q and NIDDM (Froguel et al., 1992; Vionnet et al., 1992), many studies have shown several mutations in different exons of the GCK gene (Osbak et al., 2009). In this report, we describe three new mutations identified in the GCK gene and also a premature stop codon, previously identified in Italy (Massa et al., 2001), in 23 probands (19%) from a Brazilian family throughout four generations. Gene 512 (2013) 486–491 Abbreviations: MODY, Maturity Onset Diabetes of the Young; GCK, glucokinase; PCR, Polymerase Chain Reaction; RFLP, Restriction Fragment Length Polymorphism; OMIM, Online Mendelian Inheritance in Men; HNF1A, hepatocyte nuclear factor-1-alpha; PDX1, homeobox protein-1; NIDDM, non-insulin-dependent diabetes mellitus; IC, informed consent; ICAs, C-peptide and islet cell antibodies; IFCC-HbA1c, glycated hemoglobin; FBG, fasting blood glucose. ⁎ Correspondence to: A.J. Mota, Departamento de Biociências e Diagnóstico Oral, Faculdade de Odontologia de São José dos Campos, Universidade Estadual Paulista “Júlio de Mesquita Filho” (UNESP), Av. Francisco J. Longo, 777, Jardim São Dimas, 12245-000, São José dos Campos, SP, Brazil. Tel./fax: +55 3905 5153. ⁎⁎ Correspondence to: F.F. Costa, Cancer Biology and Epigenomics Program, Children's Hospital of Chicago Research Center and Department of Pediatrics, Northwestern University's Feinberg School of Medicine, 2430 N. Halsted St., Box 220, Chicago, IL 60614, USA. Tel.: +1 773 880 4000x57312; fax: +1 773 7556551. E-mail addresses: adolfo.mot@gmail.com (A.J. Mota), fcosta@childrensmemorial.org, fcosta@datagenno.com (F.F. Costa). 0378-1119/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.gene.2012.10.013 Contents lists available at SciVerse ScienceDirect Gene journal homepage: www.elsevier.com/locate/gene