High frequency of mutations in the HNF-1α gene in non-obese patients with diabetes of youth in Japanese and identification of a case of digenic inheritance

Abstract Aims/hypothesis. There is an emerging epidemic of Type II (non-insulin-dependent) diabetes mellitus of youth in Japan and in many other developed countries. The aim of this study was to determine the prevalence of mutations in the hepatocyte nuclear factor (HNF)-1α gene (TCF1) in a large group of Japanese patients with early-onset non-Type I (insulin-dependent) diabetes mellitus. Since approximately 20% of Caucasian patients with HNF-1α mutations have been shown to be obese or overweight, we also examined the association of genetic variations in TCF1 with body weight in Japanese subjects. Methods. We examined 203 patients with non-Type 1 diabetes who had been diagnosed before they reached 15 years of age. Ten exons and flanking introns of TCF1 of these patients were directly sequenced for mutations. Results. We found 14 different mutations in 18 patients (8.9%), including one that was found to be de novo. The patients with the mutations had lower BMI (20.1±3.0 kg/m2) at diagnosis than the patients without them (24.5±6.0 kg/m2) (p=0.0024). All of the patients with the mutations, except for one, Y120, had normal body weight (BMI<25 kg/m2); the frequency of HNF-1α mutations in the non-obese patients of this study was 17% (17/101). Patient Y120, who had atypical symptoms of mild obesity and insulin resistance at diagnosis, was found to have inherited an additional mutation in an obesity-related gene. Conclusion/interpretation. A considerable number of non-obese Japanese patients with non-Type 1 diabetes of youth have HNF-1α-deficient diabetes. Lack of obesity could well be a characteristic feature of this form of diabetes.