• Clinical endocrinology · Oct 2007

    Multicenter Study

    Mutations in GCK and HNF-1alpha explain the majority of cases with clinical diagnosis of MODY in Spain.

    • Itziar Estalella, Itxaso Rica, Guiomar Perez de Nanclares, Jose Ramon Bilbao, Jose Antonio Vazquez, Jose Ignacio San Pedro, Maria Angeles Busturia, Luis Castaño, and Spanish MODY Group.
    • Endocrinology and Diabetes Research Group, Hospital de Cruces, Barakaldo, Basque Country, Spain.
    • Clin. Endocrinol. (Oxf). 2007 Oct 1; 67 (4): 538-46.

    ObjectiveThe aim of this study was to group patients with MODY (maturity-onset diabetes of the young) according to the genetic alterations underlying the disease and to investigate their clinical characteristics.Patients And MethodsMolecular analysis of GCK (MODY2), HNF-1alpha (MODY3), HNF-4alpha (MODY1) and HNF-1beta (MODY5) genes was performed by DNA sequencing in 95 unrelated index probands (47M/48F; mean age 9.9 +/- 5.2 years) with clinical diagnosis of MODY. After classification into MODY subtypes according to the genetic alterations, clinical characteristics were compared between the groups.ResultsSeventy-six families were shown to carry mutations in GCK (34 of them previously unreported), eight families presented HNF-1alpha mutations, and a large genomic rearrangement in HNF-1beta was found in a family. No alteration was found in HNF-4alpha. Thus, relative frequencies in the group studied were 80% MODY2, 8.5% MODY3 and 1% MODY5. Comparison of clinical parameters according to genetic status showed significant differences between MODY2 and MODY3 patients in age at diagnosis (9.4 +/- 5.4 years vs. 12.7 +/- 4.6 years), diagnosis (impaired glucose tolerance vs. diabetes), diagnostic test used (OGTT vs. fasting glucose), treatment (diet and exercise vs. insulin/oral antidiabetic agents) and birth weight (2.96 +/- 0.44 kg vs. 3.40 +/- 0.67 kg).ConclusionAlmost 90% of the MODY cases in the group studied are explained by mutations in the major genes GCK (MODY2) and HNF-1alpha(MODY3), although differences in the relative prevalence of each form could be partly due to patient referral bias (paediatric vs. adult). In general, patients with MODY2 were diagnosed at an earlier age in life than MODY3 patients and had a milder form of diabetes. Moreover, the majority of patients with MODY2 mutations were treated with diet whereas half of MODY3 patients received pharmacological treatment.

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