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Background: Maturity-onset diabetes of the young 2 (MODY2) is a form of diabetes that is clinically characterized by early age at onset and mild hyperglycemia, and has a low risk of late complications. It is often underdiagnosed due to its mild symptoms. To date, over 600 different GCK/MODY2 mutations have been reported. Despite only a few de novo mutations having been described, recent studies have reported the detection of a higher frequency of this kind of mutation. Therefore, de novo mutations could be more frequent than previously described. Even though common recommendations regarding the diagnosis of monogenic diabetes include the existence of a strong family history of diabetes, here we describe the study of mutations in two families with a symptomatic individual with clear clinical features of MODY2 but without any family history of diabetes.Methods: Genetic diagnosis in a group of participants with MODY2 characteristics was carried out by direct sequencing of coding regions of the GCK gene and analysis of mutations found using bioinformatics tools.Results: We found two de novo mutations, one of them novel, constituting 14.29% of all the participants who were phenotyped as MODY2.Conclusions: The number of mutations in GCK/MODY2 or even other MODY-related genes is undoubtedly underestimated, as accepted criteria for performing genetic tests include family history of the pathology. These cases illustrate the value of analyzing the GCK gene in patients with clinical features of MODY2, even in the absence of family history of the condition as it is essential for establishing the correct treatment. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: There are at least six subtypes of Maturity Onset Diabetes of the Young (MODY) with distinctive genetic causes. MODY 3 is caused by mutations in HNF1A gene, an insulin transcription factor, so mutations in this gene are associated with impaired insulin secretion. MODY 3 prevalence differs according to the population analyzed, but it is one of the most frequent subtypes. Therefore, our aims in this work were to find mutations present in the HNF1A gene and provide information on their prevalence. Material and methods: Mutations screening was done in a group of 80 unrelated patients (average age 17.1 years) selected by clinical characterization of MODY, by SSCP electrophoresis followed by sequenciation. Results: We found eight mutations, of which six were novel and four sequence variants, which were all novel. Therefore the prevalence of MODY 3 in this group was 10%. Compared clinical data between the non-MODY 3 patients and the MODY 3 diagnosed patients did not show any significant difference. Discussion: Eight patients were diagnosed as MODY 3 and new data about the prevalence of that subtype is provided. Our results contribute to reveal novel mutations, providing new data about the prevalence of that subtype. [Copyright &y& Elsevier]

Background: The different clinical presentations of latent autoimmune diabetes in adults (LADA) and type 1 diabetes mellitus may be the result of susceptibility genes in determining the mode of onset. We analyzed the 5' polymorphisms of the insulin mini-satellite region (INS), a variable number of tandem repeats (VNTR) [repeat units; RU]. We evaluated the association of the different INS-VNTR alleles in patient susceptibility to LADA autoimmune diabetes. To our knowledge, this constitutes the first study of this kind performed in a Caucasian population., Methods: From an group of 160 Argentinean patients previously characterized as having LADA, we selected 44 patients who presented with humoral autoimmunity for genotyping and compared them to 88 patients with type 1 diabetes and 138 healthy individuals. The INS-VNTR allele classes were determined by Southern blotting (class I: 21-44RU; class III: 138-159RU). Subjects with class I alleles were further studied using PCR amplification to determine the exact length of the alleles (short 1S: 22-37RU; medium 1M: 38-41RU; large 1L: 42-43RU). Allelic and genotype frequencies were estimated by chi(2) tests for independence with 2 x 2 contingency tables and the relative risks (RR) were determined using GraphPad InStat software., Results: We observed differential associations among the class I alleles when comparing patients with LADA (80.6%) and type 1 diabetes (81.3%) with the controls (70%; p < 0.005). This increase was largely due to the high frequency of the 1S/S genotype (63.6% LADA vs 37% controls, with a p-value of 0.0019 [p1]; 53.4% type 1 diabetes vs 37% controls, with a p-value of 0.0149 [p2]). Remarkably, all LADA patients genotyped as class I homozygous had the shorter (S) class I allele (100%). Differences in the overall 1S distribution were observed: in LADA the 94.4% of the alleles were equal to or smaller than 35RU, while in patients with type 1 diabetes it was 78.3% and in controls 74.1%. Moreover, the relative risks associated with the 1S/S genotype for patients with LADA showed a substantial increase with respect to those with type 1 diabetes (52%) when we compare them to the controls (1S/S LADA/control, 2.282 [RR1] vs type 1 diabetes/control, 1.497 [RR2])., Conclusion: The presence of the 1S allele could be considered a risk factor in LADA patients, as previously reported for type 1 diabetes. The class I INS-VNTR allele in LADA increases genetic susceptibility to disease development.

Maturity onset diabetes of the young (MODY) is caused by mutations in at least six different genes, including the glucokinase gene (MODY 2) and genes encoding the tissue-specific transcription factors (MODY 1 and MODY 3-6). To determine the presence of mutations in MODY 2 in four members of a family who have the clinical characteristics of MODY, we performed polymerase chain reaction and single strand conformation polymorphism screening, followed by DNA sequencing. We found a novel mutation which consisted of the deletion of a cytosine in the position 2 of the exon 5 codon 168. This mutation produced a frame shift which determines a stop codon at position 203 in exon 6. The identification of a mutation in glucokinase gene and transcription factor genes in patients with early-onset diabetes confirms the diagnosis of MODY and has important implications for clinical management.