Analysis of a non-functional HNF-1 alpha (TCF1) mutation in Japanese subjects with familial type 1 diabetes

Mutations in the transcription factor hepatocyte nuclear factor-1 alpha (HN F-1 alpha; gene symbol TCF1) cause maturity onset diabetes of the young typ e 3 (MODY3), a form of diabetes mellitus characterized by autosomal dominan t inheritance, early onset, and pancreatic beta -cell dysfunction. Recent g enetic studies, however, also found mutations in patients diagnosed with id iopathic (non autoimmune based) type 1 diabetes. We identified a novel fram eshift mutation (142delG) in the TCF1 gene in a family with a strong family history of type I diabetes and examined the functional proper ties of the mutant HNF 1 alpha The expression of the mutant protein was not detected in COS-7 cells by Western blot analysis after transfection of the mutant cDNA . This is the first case of an unstable mutant HNF-1 alpha protein. Reporte r gene analysis indicated that the mutant HNF-1 alpha had no transactivatio n activity in HeLa and MIN6 cells. Haploinsufficiency for HNF-1 alpha may l ead to severe forms of diabetes like type 1 diabetes. Hum Mutat 18:345-351, 2001. (C) 2001 Wiley-Liss, Inc.