Maturity-Onset Diabetes of the Young (MODY) in Portugal: Novel GCK, HNFA1 and HNFA4 Mutations

Maturity-onset diabetes of the young (MODY) is a frequently misdiagnosed type of diabetes, which is characterized by early onset, autosomal dominant inheritance, and absence of insulin dependence. The most frequent subtypes are due to mutations of the <i>GCK</i> (MODY 2), <i>HNF1A</i> (MODY 3), and <i>HNF4A</i> (MODY 1) genes. We undertook the first multicenter genetic study of MODY in the Portuguese population. The <i>GCK</i>, <i>HNF1A</i><i>,</i> and <i>HNF4A</i> genes were sequenced in 46 unrelated patients that had at least two of the three classical clinical criteria for MODY (age at diagnosis, family history, and clinical presentation). The functional consequences of the mutations were predicted by bioinformatics analysis. Mutations were identified in 23 (50%) families. Twelve families had mutations in the <i>GCK</i> gene, eight in the <i>HNF1A</i> gene, and three in the <i>HNF4A</i> gene. These included seven novel mutations (<i>GCK</i> c.494T>C, <i>GCK</i> c.563C>G, <i>HNF1A</i> c.1623G>A, <i>HNF1A</i> c.1729C>G, <i>HNF4A</i> c.68delG, <i>HNF4A</i> c.422G>C, <i>HNF4A</i> c.602A>C). Mutation-positive patients were younger at the time of diagnosis when compared to mutation-negative patients (14.3 vs. 23.0 years, <i>p</i> = 0.011). This study further expands the spectrum of known mutations associated with MODY, and may contribute to a better understanding of this type of diabetes and a more personalized clinical management of affected individuals.