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-α (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 dimerization and 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 = 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 = 10−4). Patients with missense mutations affecting the three isoforms were younger at diagnosis than those with missense mutations involving one or two isoforms (P = 0.03).

CONCLUSIONS—These data show that part of the variability of the clinical expression in MODY3 patients may be explained by the type and the location of HNF1A mutations. These findings should be considered in studies for the search of additional modifier genetic factors.

Heterozygous mutations in the hepatocyte nuclear factor 1-α (HNF1A) gene cause maturity-onset diabetes of the young (MODY)-3 (1,2). 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 (36).

The 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 heterozygous mutations, which affect estrogen metabolism, may increase the incidence of hepatocellular adenomas in women with MODY3 (13). The molecular characteristics of the HNF1A mutation may also play a role in the severity of the disease. About 200 different mutations have been reported in HNF1A (14). HNF1A is composed of three functional domains, and three isoforms are generated by alternative splicing, with different transcriptional properties and tissue expression patterns (15,16). A recent analysis of the HNF1A mutation spectrum showed no correlation between the age of onset of diabetes and the type of the mutation (16). An older age of onset was observed in MODY3 patients carrying a HNF1A missense mutation affecting specifically the HNF1A(A) isoform, which is highly expressed in the fetal pancreas (16).

Here, we describe the spectrum of HNF1A mutations identified in 356 unrelated MODY3 patients, and we show relationships between age at diagnosis of diabetes and the type and position of the mutations.

Patients.

This study includes 356 unrelated patients (87% Euro-Caucasians, 60% women) who had been referred for genetic testing from 1998 to 2007 and in whom a HNF1A mutation was identified. All patients gave written informed consent.

Mutation analysis.

Several criteria were used to ascertain that the novel mutations identified in the present study were pathogenic: nature of the amino acid change, conservation of the residue across species, absence of the mutation in 300 control subjects of Euro-Caucasian origin, and cosegregation of the mutation with young-onset diabetes, when relatives were available.

The molecular spectrum of HNF1A mutations was analyzed according to three criteria. First, mutations were classified into two groups according to their predicted functional consequences. One group included missense mutations resulting in amino acid changes, and the second included nonsense, small insertions/deletions, or splicing mutations, predicted to generate premature stop codons (referred to as “truncating mutations”). Second, mutations were analyzed according to the three HNF1A functional domains: NH2-terminal dimerization domain (amino acids 1–32), DNA-binding domain (amino acids 91–281), and COOH-terminal transactivation domain (282–631) (Fig. 1A) (17). Third, mutations were analyzed according to the affected isoforms of HNF1A. The HNF1A(A) isoform is the full-length transcript comprising the 10 exons, whereas HNF1A(B) and HNF1A(C) isoforms result from alternative splicing and contain the first seven and first six exons, respectively (Fig. 1B). Three groups of mutations were considered: mutations located in exons 1–6, affecting the three isoforms; mutations located in exon 7, affecting isoforms HNF1A(A) and (B); mutations located in exons 8–10, involving only the HNF1A(A) isoform.

Statistical analysis.

Age at diagnosis is reported as median and range. Data were compared with the Mann-Whitney and the Kruskall-Wallis tests. Statistical analyses were performed with GraphPad InStat (GraphPad Software, San Diego, CA).

Characteristics of the HNF1A mutational spectrum.

Among the 356 unrelated patients, 169 HNF1A mutations were identified. Fifty-one have previously been reported, whereas 118 are novel. The 51 known mutations were detected in 200 patients (supplementary Table [available at http://dx.doi.org/10.2337/db07-0859]). By contrast, the 118 novel mutations were mainly private mutations (97 of 118, 82%) (Table 1).

There were 201 (56.5%) missense and 155 (43.5%) truncating mutations (103 small insertion/deletion mutations, 31 nonsense mutations, and 21 splicing defects).

The same numbers of mutations affected the dimerization and DNA-binding domains (the two structurally major domains) and the transactivation domain (179 and 177 cases, respectively). However, missense mutations were much more frequent than truncating ones in the dimerization and DNA-binding domains (74% were missense mutations), while the opposite was noted in the transactivation domain (62% were truncating mutations) (Fig. 1A). The distribution was the same when considering only distinct mutations (not shown).

A large majority (83%) of the mutations were located in exons 1–6, thus affecting the three HNF1A isoforms; 13% of the mutations, located in exons 8–10, specifically affected the HNF1A(A) isoform; and 4% were located in exon 7, affecting isoforms HNF1A(A) and (B). This distribution within the isoforms was very similar when considering either missense or truncating mutations and when considering all or distinct mutations (Fig. 1B).

Age at diagnosis of diabetes according to the type and the position of the HNF1A mutations.

Age at diagnosis of diabetes was available for 352 patients. Median age at diagnosis was lower by 4 years in patients with truncating mutations than in those with missense mutations (18 vs. 22 years respectively, P = 0.005).

There was no difference in the age at diagnosis according to the location of the mutation within the dimerization/DNA-binding or transactivation domains (19 and 21.5 years, respectively) (Table 2). However, when both the type of the mutation and its position within the functional domains were considered, marked differences appeared. First, truncating mutations were associated with a lower age at diagnosis than missense ones when they affected the transactivation domain (19 vs. 30 years, P < 10−4). By contrast, age at diagnosis was similar for truncating and missense mutations of the dimerization/DNA binding domain (18 and 20 years, respectively). Second, missense mutations affecting the dimerization/DNA-binding domains were associated with a lower age at diagnosis than missense mutations affecting the transactivation domain (20 vs. 30 years, P = 10−4).

We then analyzed the age at diagnosis according to the isoforms affected by the mutation. Patients carrying a mutation affecting the three HNF1A isoforms had a younger age at onset of diabetes (19 years) than those with a mutation affecting isoforms A and B (29 years) or a mutation affecting only the HNF1A(A) isoform (24 years, P = 0.03 by ANOVA). No difference in the age at diagnosis was observed in patients with truncating mutations, regardless of the affected isoforms. By contrast, patients with missense mutations affecting the three isoforms were much younger at diagnosis (20 years) than those with missense mutations altering one or two isoforms (31 and 33 years, respectively, P = 0.006 by ANOVA).

Because the functional domains and the isoform structure are overlapping within the first six exons (Fig. 1), we compared age at diagnosis associated with missense mutations located in the dimerization/DNA-binding domains (amino acids 1–281) with that associated with missense mutations located in the part of the transactivation domain common to the three isoforms (amino acids 282–437). Age at diagnosis was lower in the former than in the latter (20 vs. 26.5 years, respectively, P = 0.015).

This large series of HNF1A mutations in 356 unrelated MODY3 patients emphasizes the high allelic heterogeneity of HNF1A. Among the 169 distinct mutations, 118 were not reported in a recent update (14). The large majority (82%) of the novel mutations were private. The type of mutations differed markedly within functional domains: in the dimerization/DNA-binding domain, 74% of the mutations were missense, whereas in the transactivation domain, truncating mutations were predominant (62%). A similar distribution of HNF1A mutations has previously been reported (14). Some missense mutations may have mild functional consequences on the protein, and their clinical expression may depend on the functional importance of the affected domain. Thus, some missense mutations of the transactivation domain may not be associated with overt diabetes or lead to a milder phenotype suggesting type 2 diabetes. In patients with truncating mutations, the mean age at diagnosis of diabetes was 18. This is similar to that previously reported in a large series of MODY3 patients (16) and suggests that truncating mutations have similar functional consequences. Nonsense-mediated decay may be the common mechanism leading to this homogenous phenotype through haplo-insufficiency (18). In patients with missense mutations, diabetes was diagnosed later (by 4 years on average) than in those with truncating mutations. This is in contrast with previous results that did not show relationship between the type of the mutations and age at onset (16). However, we only studied probands, while in the study by Harries et al., 55% of the MODY3 patients were relatives (16). We suggest that analyzing relatives together with the probands may introduce a bias toward the inclusion of young subjects through family screening. This would decrease the median age at diagnosis. Moreover, our diagnosis criteria are less restrictive than those often used to raise the diagnosis of MODY3, since we included probands with an age of onset of diabetes above 25 years.

Further analysis combining the type of the mutation and its location within the functional domains revealed striking differences in the age at diagnosis of diabetes. Diabetes was revealed 10 years earlier in patients carrying missense mutations located in the dimerization/DNA-binding domains than in those with a missense mutation in the transactivation domain. We hypothesize that missense mutations affecting the dimerization/DNA-binding domain have more severe functional consequences, such as impaired DNA-binding and protein stability (19).

Recently, it has been shown that the age at onset of diabetes may be influenced by the position of the mutation relative to HNF1A isoforms. Missense mutations located in exons eight to 10, that are specific of the HNF1A(A) isoform, were associated with an older age of onset (16). The authors suggested that this was due to differences in the expression level of the various isoforms in fetal and adult pancreas. We found that patients harboring missense mutations located in exon 7 or in exons 8–10 were diagnosed more than 10 years later than those with mutations in exons 1–6. However, since exons 1–6 include the dimerization and DNA-binding domains, the observed effect on age at diagnosis could be due either to involvement of the three isoforms or to the position of the mutation within the dimerization/DNA-binding domains (Fig. 1). To distinguish between these two possibilities, we compared mutations affecting the dimerization/DNA-binding domain to that affecting the first part of the transactivation domain, and we observed a younger age at onset in the former than in the latter. Thus, the location of the mutation within a domain crucial for the function of the protein overcomes the fact that the mutation affects the three isoforms of HNF1A. This was confirmed by a multivariate analysis (not shown).

The wide variability of MODY3 phenotype has suggested the role of modifier genes. However, such genes have not been identified yet (12). We have shown that truncating mutations, as compared with missense mutations, have an effect on the clinical expression of the disease. Moreover, in patients with missense mutations, which represent more than half of the cases, the position of the mutation relative to the functional domains of HNF1A also plays a role in the severity of the disease. We suggest that these parameters should be considered in the studies aiming at the identification of other factors that may influence the clinical expression of MODY3.

FIG. 1.

HNF1A mutational spectrum according to the genomic and isoform structures. A: The three functional domains are identified on the genomic sequence in dark gray (dimerization domain), mid-gray (DNA binding domain), and light gray (transactivation domain). Each exon is represented by a numbered box. B: The exons transcribed in the three HNF1A isoforms are indicated and colored according to the number of affected isoforms: the mid-gray boxes correspond to exons common to the three isoforms; the dotted box corresponds to exon 7 specific to the HNF1A(A) and (B) isoforms; and the white boxes correspond to exons specific to HNF1A(A). The numbers of mutations are indicated under the corresponding affected domain or isoform.

FIG. 1.

HNF1A mutational spectrum according to the genomic and isoform structures. A: The three functional domains are identified on the genomic sequence in dark gray (dimerization domain), mid-gray (DNA binding domain), and light gray (transactivation domain). Each exon is represented by a numbered box. B: The exons transcribed in the three HNF1A isoforms are indicated and colored according to the number of affected isoforms: the mid-gray boxes correspond to exons common to the three isoforms; the dotted box corresponds to exon 7 specific to the HNF1A(A) and (B) isoforms; and the white boxes correspond to exons specific to HNF1A(A). The numbers of mutations are indicated under the corresponding affected domain or isoform.

TABLE 1

Description of 118 novel HNF1A mutations

LocationChange at the DNA levelChange at the protein levelMutation typeOccurrence
Exon 1 c.1A>C p.Met1Leu Missense 
Exon 1 c.22C>A p.Leu8Met Missense 
Exon 1 c.41C>T p.Ala14Val Missense 
Exon 1 c.49C>G p.Leu17Val Missense 
Exon 1 c.50T>A p.Leu17Gln Missense 
Exon 1 c.59G>C p.Gly20Ala Missense 
Exon 1 c.77T>C p.Leu26Pro Missense 
Exon 1 c.80T>C p.Ile27Thr Missense 
Exon 1 c.80T>G p.Ile27Ser Missense 
Exon 1 c.82C>T p.Gln28X Nonsense 
Exon 1 c.98C>T p.Pro33Leu Missense 
Exon 1 c.202C>T p.Arg68Trp Missense 
Exon 1 c.206delG p.Gly69fs Deletion 
Exon 1 c.217G>T p.Glu73X Nonsense 
Exon 1 c.225C>A p.Asp75Glu Missense 
Exon 1 c.259A>T p.Lys87X Nonsense 
Exon 1 c.282_283insT p.Glu95X Nonsense 
Exon 1 c.319C>G p.Leu107Val Missense 
Exon 1 c.326delA p.Gln109fs Deletion 
Exon 2 c.346G>A p.Ala116Thr Missense 
Exon 2 c.368T>G p.Leu123Arg Missense 
Exon 2 c.396G>C p.Glu132Asp Missense 
Exon 2 c.397G>T p.Val133Leu Missense 
Exon 2 c.403G>A p.Asp135Asn Missense 
Exon 2 c.410C>G p.Thr137Ser Missense 
Exon 2 c.412G>A p.Gly138Ser Missense 
Exon 2 c.427delC p.His143fs Deletion 
Exon 2 c.436_438dup p.Gln146dup Insertion 
Exon 2 c.436C>T p.Gln146X Nonsense 
Exon 2 c.442C>A p.Leu148Ile Missense 
Exon 2 c.447C>G p.Asn149Lys Missense 
Exon 2 c.460A>G p.Met154Val Missense 
Exon 2 c.461T>C p.Met154Thr Missense 
Exon 2 c.461T>G p.Met154Arg Missense 
Exon 2 c.517G>A p.Val173Met Missense 
Exon 2 c.521C>T p.Ala174Val Missense 
Exon 2 c.523C>T p.Gln175X Nonsense 
Intron 2 c.526 + 1G>C  Splicing Defect 
Intron 2 c.526 + 5G>A  Splicing Defect 
Exon 3 c.586A>G p.Thr196Ala Missense 
Exon 3 c.614delA p.Lys205fs Deletion 
Exon 3 c.620_621insG p.Gly207fs Insertion 
Exon 3 c.650C>G p.Ala217Gly Missense 
Exon 3 c.676A>G p.Lys226Glu Missense 
Exon3 c.682_683insG p.Glu228fs Insertion 
Exon 3 c.682G>A p.Glu228Lys Missense 
Exon 3 c.696_697insA p.Val233fs Insertion 
Exon 3 c.704_705insA p.Cys236fs Insertion 
Exon 3 c.711_713+6del p.Arg238fs Deletion 
Intron 3 c.713+1G>C  Splicing Defect 
Exon 4 c.715G>A p.Ala239Thr Missense 
Exon 4 c.722G>A p.Cys241Tyr Missense 
Exon 4 c.732A>T p.Arg244Ser Missense 
Exon 4 c.732_733delAG p.Ser247fs Deletion 
Exon 4 c.737T>G p.Val246Gly Missense 
Exon 4 c.746_747insC p.Gln250fs Insertion 
Exon 4 c.763G>A p.Gly255Ser Missense 
Exon 4 c.785_786insT p.Arg263fs Insertion 
Exon 4 c.790G>T p.Val264Phe Missense 
Exon 4 c.798C>G p.Asn266Lys Missense 
Exon 4 c.814C>A p.Arg272Ser Missense 
Exon 4 c.827C>G p.Ala276Gly Missense 
Exon 4 c.842T>C p.Leu281Pro Missense 
Exon 4 c.865C>T p.Pro289Ser Missense 
Exon 4 c.871C>A p.Pro291Thr Missense 
Exon 4 c.919delC p.Leu307fs Deletion 
Exon 4 c.923C>T p.Pro308Leu Missense 
Intron 4 c.955+2T>C  Splicing Defect 
Exon 5 c.959_962dupTGCG p.Tyr322fs Insertion 
Exon 5 c.965A>G p.Tyr322Cys Missense 
Exon 5 c.966T>G p.Tyr322X Nonsense 
Exon 5 c.970C>T p.Gln324X Nonsense 
Exon 5 c.984T>G p.Ser328Arg Missense 
Exon 5 c.1017delT p.Leu341X Nonsense 
Exon 5 c.1059_1060insC p.Thr354fs Insertion 
Exon 5 c.1080_1081dupCA p.Ser361fs Insertion 
Exon 6 c.1118C>G p.Ala373Gly Missense 
Exon 6 c.1135C>A p.Pro379Thr Missense 
Exon 6 c.1135C>G p.Pro379Ala Missense 
Exon 6 c.1135C>T p.Pro379Ser Missense 
Exon 6 c.1136delC p.Pro379fs Deletion 
Exon 6 c.1137_1138insT p.Val380fs Insertion 
Exon 6 c.1165T>G p.Leu389Val Missense 
Exon 6 c.1195C>T p.Gln399X Nonsense 
Exon 6 c.1226C>A p.Pro409His Missense 
Exon 6 c.1271C>T p.Pro424Leu Missense 
Intron 7 c.1502-2A>G  Splicing Defect 
Intron 7 c.1502-2A>T  Splicing Defect 
Exon 7 c.1369_1383dup p.Val462fs Insertion 
Exon 7 c.1387C>T p.Gln463X Nonsense 
Exon 7 c.1394C>T p.Ser465Phe Missense 
Exon 7 c.1394C>T p.Ser465Phe Missense 
Exon 7 c.1400C>T p.Pro467Leu Missense 
Exon 7 c.1421_1422insA p.Pro475fs Insertion 
Exon 7 c.1444_1445delAG p.Ser482fs Deletion 
Exon 7 c.1465T>G p.Phe489Val Missense 
Exon 7 c.1495C>T p.Pro499Ser Missense 
Exon 7 c.1498C>A p.His500Asn Missense 
Exon 8 c.1509C>A p.Tyr503X Nonsense 
Exon 8 c.1513C>A p.His505Asn Missense 
Exon 8 c.1522G>A p.Glu508lys Missense 
Exon 8 c.1537A>T p.Thr513Ser Missense 
Exon 8 c.1544C>A p.Thr515Lys Missense 
Exon 8 c.1573A>T p.Thr525Ser Missense 
Exon 8 c.1574C>T p.Thr525Ile Missense 
Exon 8 c.1576G>A p.Asp526Asn Missense 
Exon 8 c.1576G>T p.Asp526Tyr Missense 
Exon 8 c.1587_1588insA p.Asn529fs Insertion 
Exon 8 c.1611_1614delGCCC p.Pro538fs Deletion 
Intron 8 c.1623+2T>C  Splicing Defect 
Exon 9 c.1637A>G p.Asp546Gly Missense 
Exon 9 c.1663C>T p.Leu555Phe Missense 
Exon 9 c.1670_1685dup p.Thr557_Ala562dup Insertion 
Exon 9 c.1673_1674insC p.Ala559fs Insertion 
Exon 9 c.1762C>T p.Pro588Ser Missense 
Exon 10 c.1840_1841delAA p.Asn614fs Deletion 
Exon 10 c.1853_1854delTC p.Ile618fs Deletion 
Exon 10 c.1864_1890dup p.Ile622_Ser630dup Insertion 
LocationChange at the DNA levelChange at the protein levelMutation typeOccurrence
Exon 1 c.1A>C p.Met1Leu Missense 
Exon 1 c.22C>A p.Leu8Met Missense 
Exon 1 c.41C>T p.Ala14Val Missense 
Exon 1 c.49C>G p.Leu17Val Missense 
Exon 1 c.50T>A p.Leu17Gln Missense 
Exon 1 c.59G>C p.Gly20Ala Missense 
Exon 1 c.77T>C p.Leu26Pro Missense 
Exon 1 c.80T>C p.Ile27Thr Missense 
Exon 1 c.80T>G p.Ile27Ser Missense 
Exon 1 c.82C>T p.Gln28X Nonsense 
Exon 1 c.98C>T p.Pro33Leu Missense 
Exon 1 c.202C>T p.Arg68Trp Missense 
Exon 1 c.206delG p.Gly69fs Deletion 
Exon 1 c.217G>T p.Glu73X Nonsense 
Exon 1 c.225C>A p.Asp75Glu Missense 
Exon 1 c.259A>T p.Lys87X Nonsense 
Exon 1 c.282_283insT p.Glu95X Nonsense 
Exon 1 c.319C>G p.Leu107Val Missense 
Exon 1 c.326delA p.Gln109fs Deletion 
Exon 2 c.346G>A p.Ala116Thr Missense 
Exon 2 c.368T>G p.Leu123Arg Missense 
Exon 2 c.396G>C p.Glu132Asp Missense 
Exon 2 c.397G>T p.Val133Leu Missense 
Exon 2 c.403G>A p.Asp135Asn Missense 
Exon 2 c.410C>G p.Thr137Ser Missense 
Exon 2 c.412G>A p.Gly138Ser Missense 
Exon 2 c.427delC p.His143fs Deletion 
Exon 2 c.436_438dup p.Gln146dup Insertion 
Exon 2 c.436C>T p.Gln146X Nonsense 
Exon 2 c.442C>A p.Leu148Ile Missense 
Exon 2 c.447C>G p.Asn149Lys Missense 
Exon 2 c.460A>G p.Met154Val Missense 
Exon 2 c.461T>C p.Met154Thr Missense 
Exon 2 c.461T>G p.Met154Arg Missense 
Exon 2 c.517G>A p.Val173Met Missense 
Exon 2 c.521C>T p.Ala174Val Missense 
Exon 2 c.523C>T p.Gln175X Nonsense 
Intron 2 c.526 + 1G>C  Splicing Defect 
Intron 2 c.526 + 5G>A  Splicing Defect 
Exon 3 c.586A>G p.Thr196Ala Missense 
Exon 3 c.614delA p.Lys205fs Deletion 
Exon 3 c.620_621insG p.Gly207fs Insertion 
Exon 3 c.650C>G p.Ala217Gly Missense 
Exon 3 c.676A>G p.Lys226Glu Missense 
Exon3 c.682_683insG p.Glu228fs Insertion 
Exon 3 c.682G>A p.Glu228Lys Missense 
Exon 3 c.696_697insA p.Val233fs Insertion 
Exon 3 c.704_705insA p.Cys236fs Insertion 
Exon 3 c.711_713+6del p.Arg238fs Deletion 
Intron 3 c.713+1G>C  Splicing Defect 
Exon 4 c.715G>A p.Ala239Thr Missense 
Exon 4 c.722G>A p.Cys241Tyr Missense 
Exon 4 c.732A>T p.Arg244Ser Missense 
Exon 4 c.732_733delAG p.Ser247fs Deletion 
Exon 4 c.737T>G p.Val246Gly Missense 
Exon 4 c.746_747insC p.Gln250fs Insertion 
Exon 4 c.763G>A p.Gly255Ser Missense 
Exon 4 c.785_786insT p.Arg263fs Insertion 
Exon 4 c.790G>T p.Val264Phe Missense 
Exon 4 c.798C>G p.Asn266Lys Missense 
Exon 4 c.814C>A p.Arg272Ser Missense 
Exon 4 c.827C>G p.Ala276Gly Missense 
Exon 4 c.842T>C p.Leu281Pro Missense 
Exon 4 c.865C>T p.Pro289Ser Missense 
Exon 4 c.871C>A p.Pro291Thr Missense 
Exon 4 c.919delC p.Leu307fs Deletion 
Exon 4 c.923C>T p.Pro308Leu Missense 
Intron 4 c.955+2T>C  Splicing Defect 
Exon 5 c.959_962dupTGCG p.Tyr322fs Insertion 
Exon 5 c.965A>G p.Tyr322Cys Missense 
Exon 5 c.966T>G p.Tyr322X Nonsense 
Exon 5 c.970C>T p.Gln324X Nonsense 
Exon 5 c.984T>G p.Ser328Arg Missense 
Exon 5 c.1017delT p.Leu341X Nonsense 
Exon 5 c.1059_1060insC p.Thr354fs Insertion 
Exon 5 c.1080_1081dupCA p.Ser361fs Insertion 
Exon 6 c.1118C>G p.Ala373Gly Missense 
Exon 6 c.1135C>A p.Pro379Thr Missense 
Exon 6 c.1135C>G p.Pro379Ala Missense 
Exon 6 c.1135C>T p.Pro379Ser Missense 
Exon 6 c.1136delC p.Pro379fs Deletion 
Exon 6 c.1137_1138insT p.Val380fs Insertion 
Exon 6 c.1165T>G p.Leu389Val Missense 
Exon 6 c.1195C>T p.Gln399X Nonsense 
Exon 6 c.1226C>A p.Pro409His Missense 
Exon 6 c.1271C>T p.Pro424Leu Missense 
Intron 7 c.1502-2A>G  Splicing Defect 
Intron 7 c.1502-2A>T  Splicing Defect 
Exon 7 c.1369_1383dup p.Val462fs Insertion 
Exon 7 c.1387C>T p.Gln463X Nonsense 
Exon 7 c.1394C>T p.Ser465Phe Missense 
Exon 7 c.1394C>T p.Ser465Phe Missense 
Exon 7 c.1400C>T p.Pro467Leu Missense 
Exon 7 c.1421_1422insA p.Pro475fs Insertion 
Exon 7 c.1444_1445delAG p.Ser482fs Deletion 
Exon 7 c.1465T>G p.Phe489Val Missense 
Exon 7 c.1495C>T p.Pro499Ser Missense 
Exon 7 c.1498C>A p.His500Asn Missense 
Exon 8 c.1509C>A p.Tyr503X Nonsense 
Exon 8 c.1513C>A p.His505Asn Missense 
Exon 8 c.1522G>A p.Glu508lys Missense 
Exon 8 c.1537A>T p.Thr513Ser Missense 
Exon 8 c.1544C>A p.Thr515Lys Missense 
Exon 8 c.1573A>T p.Thr525Ser Missense 
Exon 8 c.1574C>T p.Thr525Ile Missense 
Exon 8 c.1576G>A p.Asp526Asn Missense 
Exon 8 c.1576G>T p.Asp526Tyr Missense 
Exon 8 c.1587_1588insA p.Asn529fs Insertion 
Exon 8 c.1611_1614delGCCC p.Pro538fs Deletion 
Intron 8 c.1623+2T>C  Splicing Defect 
Exon 9 c.1637A>G p.Asp546Gly Missense 
Exon 9 c.1663C>T p.Leu555Phe Missense 
Exon 9 c.1670_1685dup p.Thr557_Ala562dup Insertion 
Exon 9 c.1673_1674insC p.Ala559fs Insertion 
Exon 9 c.1762C>T p.Pro588Ser Missense 
Exon 10 c.1840_1841delAA p.Asn614fs Deletion 
Exon 10 c.1853_1854delTC p.Ile618fs Deletion 
Exon 10 c.1864_1890dup p.Ile622_Ser630dup Insertion 

HNF1A mutation nomenclature according to accession number NM_000545.3.

TABLE 2

Age at diagnosis of diabetes in MODY3 patients according to type and position of HNF1A mutations

Age at diagnosis of diabetes in MODY3 patients according to type and position of HNF1A mutations
Age at diagnosis of diabetes in MODY3 patients according to type and position of HNF1A mutations

Age at diagnosis indicated as median (range). Comparisons between groups were performed using the Mann-Witney test or Kruskal-Wallis test where appropriate.

*

Dimerization/DNA-binding domain, amino acids 1–281; transactivation domain, amino acids 282–631.

Published ahead of print at http://diabetes.diabetesjournals.org on 14 November 2007. DOI: 10.2337/db07-0859.

Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0859.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We thank all participants of the French Study Group of MODY for referring the patients and communication of clinical data. We thank Sandrine Beaufils, Florence Bellanger, Séverine Clauin, Sandrine Gobrecht, Gwendoline Leroy, and Christelle Vaury of the Molecular Genetics Laboratory for MODY genetic screening.

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