MUTATIONS IN THE HEPATOCYTE NUCLEAR FACTOR-1-ALPHA MODY3 GENE IN JAPANESE SUBJECTS WITH EARLY-ONSET AND LATE-ONSET NIDDM/

Recent studies have shown that mutations in the hepatocyte nuclear fac tor (HNF)-1 alpha gene are the cause of maturity-onset diabetes of the young type 3 (MODY3). We have screened 193 unrelated Japanese subject s with NIDDM for mutations in this gene: 83 with early-onset NIDDM (di agnosis at <30 years of age) and 110 with late-onset NIDDM (diagnosis greater than or equal to 30 years of age). AU of the members of the la tter group also had at least one sibling with NIDDM. The 10 exons, fla nking introns, and promoter region were amplified using polymerase cha in reaction and were sequenced directly. Mutations were found in 7 of the 83 (8%) unrelated subjects with early-onset NIDDM. The mutations w ere each different and included four missense mutations (L12H, R131Q, K205A, and R263C) and three frameshift mutations (P379fsdelCT, T392fsd elA, and L584S585fsin-sTC). One of the 110 subjects with late-onset NI DDM was heterozygous for the missense mutation G191D. This subject, wh o was diagnosed with NIDDM at 64 years of age, also had a brother with NIDDM (age at diagnosis, 54 years) who carried the same mutation, sug gesting that this mutation contributed to the development of NIDDM in these two siblings. None of these mutations were present in 50 unrelat ed subjects with normal glucose tolerance (100 normal chromosomes). Mu tations in the HNF-1 alpha gene occur in Japanese subjects with NIDDM and appear to be an important cause of early-onset NIDDM in this popul ation. In addition, they are present in about 1% of subjects with late -onset NIDDM.