The relative frequencies of the subtypes of maturity-onset diabetes of the young (MODY) were shown to vary greatly in studies from different populations (14). The Brazilian population has mixed ethnic background (African, Asian, European-Caucasian of several different countries of origin, and Indigenous), and little is known about the genetic determinants of diabetes in Brazilians. In this report, we describe the frequencies of the major MODY subtypes in a panel of 12 Brazilian families with autosomal-dominant early-onset type 2 diabetes (Fig. 1).

A total of 32 family members were studied. The age at diagnosis of diabetes was <25 years in at least one family member in 10 of the 12 families and was between 30 and 35 years in the two remaining families. The probands were five men and seven women with overt diabetes according to the revised criteria, aged 34 ± 18 years (mean ± SD), with age of diagnosis of 24 ± 13 years (range 8–50). The promoter and the coding regions of glucokinase (GCK/MODY2), hepatocyte nuclear factor 4α (HNF-4α/MODY1), and HNF-1α (MODY3) genes were screened for mutations by fluorescent-based single-strand conformational polymorphism (glucokinase only) and/or by direct sequencing. Three variants (C18R, Q59l, and D76N) in the insulin promoter factor 1 (IPF1/MODY4) gene previously found to be associated with familial diabetes were screened by polymerase chain reaction–restriction fragment–length polymorphism (5). IPF1, HNF-1β, and NeuroD1 genes were not systematically tested because they are very rare causes of MODY.

A missense mutation (GGA→GTA, G175V) in exon five and a variant in intron two (IVS2-8G→A) of the glucokinase gene were observed in the probands from kindred CAS and SAN, respectively. A missense mutation (CGG→CAG, R131Q) in exon two of the HNF-1α gene was detected in probands of two kindred (FRA and MAR). This mutation was already found to be associated with MODY in American and German kindred (6). A frameshift by the insertion of one nucleotide (P291fsinsC) in exon four of the HNF-1α gene was also observed in probands of two kindred (CAR and SES). This mutation is located in a mutational hotspot and seems to account for 20–25% of MODY3 mutations in several Caucasian populations (2,4,6). Mutations in the HNF-4α gene were not detected in our sample. The D76N variant in exon one of IPF1 was observed in the proband of kindred MAR, who also carried the HNF-1α R131Q mutation. It was suggested that the 76N allele has decreased transcriptional activity and could predispose to late-onset type 2 diabetes in a polygenic context (5), but these results were not confirmed in another study (7). The glucokinase and HNF-1α mutations were present in all subjects with hyperglycemia and in none of the normoglycemic relatives available for testing in the respective kindred (Fig. 1). The variant in intron two of the glucokinase gene and the IPF-1 D76N variant did not cosegregate with diabetes in kindred SAN and MAR. Regarding the clinical profile of the affected family members, MODY-X (no known mutation) subjects were more often treated by insulin or oral hypoglycemic agents than MODY2 and MODY3 subjects (86 vs. 18%; Fisher’s exact test P = 0.013), suggesting that they might have more severe diabetes. Both mild (1) and severe (4) diabetes have been reported in MODY-X, which might suggest genetic heterogeneity.

The relative prevalences of MODY1, MODY2, MODY3, and MODY-X in our panel were 0, 8.3, 33.3, and 58.4%, respectively. Prevalences reported in the literature are heterogeneous, ranging from 0% (1) to 8% (4) for MODY1, 8% (3) to 63% (1) for MODY2, 21% (1) to 65% (2) for MODY3, and 16% (1) to 45% (3) for MODY-X. These heterogeneous results may reflect distinct genetic background, differences in the recruitment and ascertainment of families, or bias due to the small number of families in some of these investigations, including ours. Clinical misdiagnosis of MODY could explain the higher prevalence of MODY-X in our sample. If we apply a more stringent criterion, such as onset of diabetes before 25 years in at least two family members, the prevalences of the MODY subtypes would be 0, 12.5, 37.5 and 50%, respectively. However, the stringent criterion would have excluded the MODY3 kindred CAR.

In conclusion, mutations in the glucokinase and HNF-1α genes account for ∼42% of the cases of MODY in a panel of Brazilian families, with MODY3 being the most frequent of the two subtypes. Our data suggest that the unknown MODY-X gene(s) could account for a large proportion of MODY cases in Brazil.

Figure 1 —

Pedigrees of the 12 families. Arrows identify the probands. Squares denote male family members, and circles denote female family members. Losangles and question marks (?) denote other family members of unknown glycemic status. Ages at diagnosis of diabetes are noted under the symbols. Wt and M stand for wild type and mutant alleles of glucokinase and HNF-1α genes. P (kindred SAN) stands for the IVS2-8G→A glucokinase polymorphism. D and N (kindred MAR) are alleles of the D76N variant of IPF1 gene.

Figure 1 —

Pedigrees of the 12 families. Arrows identify the probands. Squares denote male family members, and circles denote female family members. Losangles and question marks (?) denote other family members of unknown glycemic status. Ages at diagnosis of diabetes are noted under the symbols. Wt and M stand for wild type and mutant alleles of glucokinase and HNF-1α genes. P (kindred SAN) stands for the IVS2-8G→A glucokinase polymorphism. D and N (kindred MAR) are alleles of the D76N variant of IPF1 gene.

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A.F.R. was supported by a doctoral grant from CAPES, Brasilia, Brazil.

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Address correspondence to Gilberto Velho, INSERM U-342, Hôpital Saint-Vincent-de-Paul, 82 ave. Denfert Rochereau, 75014 Paris, France. E-mail: gvelho@infobiogen.fr.