RESUMEN
AIM/HYPOTHESIS: We analysed Japanese MODY patients for mutations in the HNF-1 alpha gene. METHODS: Fifty unrelated Japanese patients with early-onset diabetes (diagnosed at 25 years of age or younger) or with a strong family history of diabetes were screened for mutations in the HNF-1 alpha gene. Functional studies of the mutant HNF-1alpha were carried out. RESULTS: We identified three new mutations in the HNF-1 alpha gene in the families with a strong family history for diabetes. One mutation (L518P519fsTCC --> A) was identified in three unrelated families, while the other two mutations (T521I and V617I) were identified in one family. We also identified the A site of the promoter (+102G-to-C), which was reported previously. We examined the functional properties of the mutant HNF-1alpha. By increasing the amount of L518P519fsTCC-->A-HNF-1alpha, increasing inhibition of the transcription of human transthyretin (TTR) was observed (up to 61% of the control). Increasing amounts of T521I-HNF-1alpha or V617I-HNF-1alpha mutant proteins increased TTR promoter transcription up to 4.3-fold and 2.4-fold, respectively, whereas both increased transcription up to 12.4-fold of the control. CONCLUSION/INTERPRETATION: The L518P519fsTCC --> A was identified for the first time and this mutation might be a common cause of Japanese MODY3 in Okinawa area. In addition, both the T521I and V617I mutations were present in two patients in the same family. Since the prevalence of these mutations is relatively high (10%, 5/50), the HNF-1 alpha gene needs to be screened for mutations in patients either with early-onset diabetes or with a strong family history for diabetes.