The Type and the Position of HNF1A Mutation Modulate Age at Diagnosis of Diabetes in Patients with Maturity-Onset Diabetes of the Young (MODY)-3

Abstract

OBJECTIVE-The clinical expression of maturity-onset diabetes of the young (MODY)-3 is highly variable. This may be due to environmental and/or genetic factors, including molecular characteristics of the hepatocyte nuclear factor 1-␣ (HNF1A) gene mutation. RESEARCH DESIGN AND METHODS-We analyzed the mutations identified in 356 unrelated MODY3 patients, including 118 novel mutations, and searched for correlations between the genotype and age at diagnosis of diabetes. RESULTS-Missense mutations prevailed in the dimerizationand DNA-binding domains (74%), while truncating mutations were predominant in the transactivation domain (62%). The majority (83%) of the mutations were located in exons 1-6, thus affecting the three HNF1A isoforms. Age at diagnosis of diabetes was lower in patients with truncating mutations than in those with missense mutations (18 vs. 22 years, P ϭ 0.005). Missense mutations affecting the dimerization/DNA-binding domains were associated with a lower age at diagnosis than those affecting the transactivation domain (20 vs. 30 years, P ϭ 10 Ϫ4 ). Patients with missense mutations affecting the three isoforms were younger at diagnosis than those with missense mutations involving one or two isoforms (P ϭ 0.03). MODY3 is characterized by a severe insulin secretion defect, a retained sensitivity to sulfonylureas, a decreased renal threshold for glucose reabsorption, and, in rare families, the occurrence of liver adenomatosis (3-6). CONCLUSIONS-TheseThe clinical expression of MODY3 is highly variable from one family to another or even within the same family (7). HNF1A mutation carriers may be normoglycemic while their siblings may be hyperglycemic at a comparable age (8). Symptoms at diagnosis may be variable. Some patients have metabolic decompensation, while in others diabetes is diagnosed by systematic screening. The severity and the course of insulin secretion defect also vary since approximately one-third of the patients are treated with insulin after 15 years of diabetes duration, whereas others control their diabetes by diet or oral hypoglycemic agents (9).As in other monogenic diseases, this phenotype variability may be explained by environmental and/or additional genetic factors. Two studies have shown that age at diagnosis of diabetes in offspring carrying a HNF1A mutation was lower by 5-10 years when maternal diabetes was diagnosed before pregnancy, suggesting the role of exposure of the fetus to maternal hyperglycemia (10,11). Modifier genetic factors may also modulate the phenotype of the disease. Age at onset of diabetes is partly inheritable within MODY3 families, and putative genetic modifier loci have been mapped but not identified yet (12). In the same vein, it has been recently shown that germ line CYP1B1 Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0859.HNF1A, hepatocyte nuclear factor 1-␣; MODY, maturity-onset diabetes of the young.

Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies

“…Individual genes can harbour hundreds of genetic variants. As an illustration, the MODY3 gene (HNF1A, the commonest monogenic cause of diabetes) has 200-300 known mutations (missense, nonsense, splicing defects, insertions and deletions) [126]. Therefore, we should expect the genetic architecture of typical type 2 diabetes to be much more complex still, and this will make it harder to identify genetic causes of the disease.…”

Response to oral gliclazide in a pre-pubertal child with hepatic nuclear factor-1 alpha maturity onset diabetes of the young

“…More than 350 mutations have been identified in the HNF-1α gene leading to variable clinical expression and age of presentation 5. HNF-1α is a protein that binds to promoter regions of other genes and activates the transcription to mRNA.…”

Clinical utility gene card for: Maturity-onset diabetes of the young

“…In contrast, patients with HNF1A truncating mutations are diagnosed at a median age of 20 years independently of the location of the mutation within HNF1A. 7,8 A similar correlation was observed with HNF4A mutations. 9…”