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

• Published in: Human mutation Vol. 18; no. 4; pp. 345 - 351
• Main Authors: Yoshiuchi, Issei, Yamagata, Kazuya, Yoshimoto, Masaaki, Zhu, Qian, Yang, Qin, Nammo, Takao, Uenaka, Rikako, Kinoshita, Ei-ichi, Hanafusa, Toshiaki, Miyagawa, Jun-ichiro, Matsuzawa, Yuji
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 01.10.2001
• Subjects: diabetes; diabetes, type 1; hepatocyte nuclear factor-1α; HNF-1α; maturity-onset diabetes of the young; MODY3; TCF1; type 1
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.1196

Mutations in the transcription factor hepatocyte nuclear factor‐1α (HNF‐1α; gene symbol TCF1) cause maturity‐onset diabetes of the young type 3 (MODY3), a form of diabetes mellitus characterized by autosomal dominant inheritance, early onset, and pancreatic β‐cell dysfunction. Recent genetic studies, however, also found mutations in patients diagnosed with idiopathic (non‐autoimmune based) type 1 diabetes. We identified a novel frameshift mutation (142delG) in the TCF1 gene in a family with a strong family history of type 1 diabetes and examined the functional properties of the mutant HNF 1α. 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‐1α protein. Reporter gene analysis indicated that the mutant HNF‐1α had no transactivation activity in HeLa and MIN6 cells. Haploinsufficiency for HNF‐1α may lead to severe forms of diabetes like type 1 diabetes. Hum Mutat 18:345–351, 2001. © 2001 Wiley‐Liss, Inc.