Abstract
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 GCK (MODY 2), HNF1A (MODY 3), and HNF4A (MODY 1) genes. We undertook the first multicenter genetic study of MODY in the Portuguese population. The GCK, HNF1A, and HNF4A 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 GCK gene, eight in the HNF1A gene, and three in the HNF4A gene. These included seven novel mutations (GCK c.494T>C, GCK c.563C>G, HNF1A c.1623G>A, HNF1A c.1729C>G, HNF4A c.68delG, HNF4A c.422G>C, HNF4A 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, p = 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.
Highlights
Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes characterized by early onset, autosomal dominant inheritance and absence of insulin dependence during a variable period of time [1].MODY is estimated to account for about 1–2% of all cases of diabetes [2]
There are several subtypes of MODY caused by mutations in at least 14 known genes (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, APPL1), which have in common a primary defect in insulin secretion associated with pancreatic beta cell dysfunction [5]
Thirteen variants have already been reported in MODY patients, namely GCK c.130G>A [15], GCK c.386G>A [16], GCK c.544G>A [17], GCK c.556C>T [18], GCK c.698G>A [19], GCK c.757G>C [20], GCK c.1099G>A [21], GCK c.1268T>A [22], HNF1A c.425C>T [23], HNF1A c.475C>T [24], HNF1A c.511C>T [23], HNF1A c.521C>T [25], and HNF1A c.607C>A [26]
Summary
MODY is estimated to account for about 1–2% of all cases of diabetes [2]. There are several subtypes of MODY caused by mutations in at least 14 known genes (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, APPL1), which have in common a primary defect in insulin secretion associated with pancreatic beta cell dysfunction [5]. Heterozygous mutations in the GCK (glucokinase) (MODY 2), HNF1A (hepatocyte nuclear factor 1 alpha) (MODY 3), and HNF4A (hepatocyte nuclear factor 4 alpha) (MODY 1) genes are the most frequent, and together they explain over 95% of the known genetic causes of MODY [6]
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