We have identified 3 novel mutations in the β-cell transcription factor IPF-1 that are associated with type 2 diabetes. All 3 mutations (C18R, D76N, and R197H) result in reduced binding of the protein to the insulin gene promoter and decreased insulin gene transcription in response to hyperglycemia. To our knowledge, this is the first evidence that mutations in IPF-1 can predispose to type 2 diabetes as well as cause MODY (6
), and the different penetrance of the mutations is reflected in their in vitro activity.
The reduction in function of the missense mutations identified in type 2 diabetic patients is not as severe as that seen with the P63fsdelC frameshift mutation, which resulted in MODY (6
). The less severe C18R and D76N mutations occur within the NH2
-terminal and first proline-rich domains of IPF-1, which primarily play a role in transcriptional activation (24
). It is surprising, therefore, that these mutations resulted in a decrease in binding activity. Nonetheless, the moderate decrease in binding activity is reflected in the effect these mutations have on insulin gene transcription, which was moderately decreased by about 25–30% compared with normal IPF-1. In addition, Lu et al. also report that mutations located NH2
-proximal to the homeodomain of IPF-1
can modulate DNA-binding activity (25
). Clinically, these mutations appeared less penetrant than the R197H mutation, which is located within the DNA-binding homeodomain of the protein and demonstrates the least activity in the functional assays (~50% of that observed with normal IPF-1).
The mechanism by which IPF-1
mutations predispose to type 2 diabetes has not been fully established. The failure to see a difference in β-cell function, despite significantly worse glucose tolerance, probably reflects the small numbers in the study rather than the presence of normal β-cell function. In addition to the insulin gene, IPF-1 also regulates the expression of other β-cell genes, including GLUT-2
), and islet amyloid polypeptide
). From our data, we cannot be certain that the reduction in insulin gene transcription in response to hyperglycemia seen in vitro is sufficient to explain the glucose intolerance and diabetes seen in subjects who are heterozygous for these mutations, because defective regulation of these other genes and insulin may also contribute to β-cell dysfunction.
To our knowledge, our studies provide the first evidence that mutations in the pancreatic transcription factor IPF-1 may predispose to type 2 diabetes. The missense mutations we have described meet many criteria for predisposing to type 2 diabetes: they reduce function in vitro; they occur within a critical gene in which a severe mutation has been shown to cause young-onset diabetes; they are associated with diabetes with a relative risk of 3.0; and they have young adult mutation carriers who are not diabetic but show impaired glucose tolerance. Genetic admixture is unlikely to be the explanation for the association with diabetes, because even with a small number of siblings and families examined, there was a trend toward association in a familial study. Additional large association studies are essential to further assess the prevalence and role of these and other IPF-1
mutations in other populations. Our reported relative risks are unreliable because of the low prevalence of the mutations, and our study used type 2 subjects selected for a strong family history of diabetes (42% had at least 1 affected parent, compared with 23% found in a community survey of 4,811 type 2 subjects) (A. Hattersley et al., unpublished observations). Only 1 previous study has looked at the role of IPF-1 in type 2 diabetes; no mutations were found in 61 Japanese subjects, but the whole gene was not sequenced (19
Although mutations were found in 2 probands who conformed to MODY criteria, in contrast to the previously described P63fsdelC (6
), C18R and D76N do not behave as highly penetrant MODY mutations, because they did not cosegregate with diabetes within families. Further evidence that these mutations do not cause MODY comes from the finding that for both mutations there are mutation carriers 25–53 years of age who are not diabetic, even after testing with an OGTT.
We conclude that mutations in IPF-1, with a moderate reduction of in vitro activity, may predispose to type 2 diabetes. To our knowledge, this is the first observation that mutations in a single gene can not only cause MODY, but can also frequently predispose to type 2 diabetes, with the phenotype depending on the severity of the mutation.