Genetic basis of early-onset, maturity-onset diabetes of the young-like diabetes in Japan and features of patients without mutations in the major MODY genes: Dominance of maternal inheritance

Background: Causative mutations cannot be identified in the majority of Asian patients with suspected maturity-onset diabetes of the young (MODY). Objectives: To elucidate the genetic basis of Japanese patients with MODY-like diabetes and gain insight into the etiology of patients without mutations in the major MODY genes. Subjects: A total of 263 Japanese patients with early-onset, non-obese, MODY-like diabetes mellitus referred to Osaka City General Hospital for diagnosis. Methods: Mutational analysis of the four major MODY genes (GCK, HNF1A, HNF4A, HNF1B) by Sanger sequencing. Mutation-positive and mutation-negative patients were further analyzed for clinical features. Results: Mutations were identified in 103 (39.2%) patients; 57 mutations in GCK; 29, HNF1A; 7, HNF4A; and 10, HNF1B. Contrary to conventional diagnostic criteria, 18.4% of mutation-positive patients did not have affected parents and 8.2% were in the overweight range (body mass index [BMI] >85th percentile). HOMA-IR at diagnosis was elevated (>2) in 15 of 66 (22.7%) mutation-positive patients. Compared with mutation-positive patients, mutation-negative patients were significantly older (P=0.003), and had higher BMI percentile at diagnosis (P=0.0006). Interestingly, maternal inheritance of diabetes was significantly more common in mutation-negative patients (P = 0.0332) and these patients had significantly higher BMI percentile as compared with mutation-negative patients with paternal inheritance (P = 0.0106). Conclusions: Contrary to the conventional diagnostic criteria, de novo diabetes, overweight, and insulin-resistance are common in Japanese patients with mutation-positive MODY. A significant fraction of mutation-negative patients had features of early-onset type 2 diabetes common in Japanese, and non-Mendelian inheritance needs to be considered for these patients.