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Original Articles

Mutation P291fsinsC in the Transcription Factor Hepatocyte Nuclear Factor-1α is Dominant Negative

  1. Kazuya Yamagata,
  2. Qin Yang,
  3. Koji Yamamoto,
  4. Hiromi Iwahashi,
  5. Jun-ichiro Miyagawa,
  6. Kohei Okita,
  7. Issei Yoshiuchi,
  8. Jun-ichi Miyazaki,
  9. Tamio Noguchi,
  10. Hiromu Nakajima,
  11. Mitsuyoshi Namba,
  12. Toshiaki Hanafusa and
  13. Yuji Matsuzawa
  1. Department of Internal Medicine, Osaka University Medical School Osaka
  2. Department of Nutrition and Physiological Chemistry, Osaka University Medical School Osaka
  3. Department of Biochemistry, Fukui Medical School Fukui, Japan
  1. Address correspondence and reprint requests to Dr. Kazuya Yamagata, Second Department of Internal Medicine, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565, Japan. E-mail: kazu{at}imed2.med.osaka-u.ac.jp
Diabetes 1998 Aug; 47(8): 1231-1235. https://doi.org/10.2337/diab.47.8.1231
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Abstract

The type 3 form of maturity-onset diabetes of the young (M0DY3) results from mutations in the gene encoding the transcription factor, hepatocyte nuclear factor-1α (HNF-1α). The mechanism by which mutations in only one allele of the HNF-1α gene impair pancreatic β-cell function is unclear. The functional form of HNF-1α is a dimer—either a homodimer or a heterodimer with the structurally related protein HNF-1β—that binds to and activates transcription of the genes whose expression it regulates. HNF-1α is composed of three functional domains: an amino-terminal dimerization domain (amino acids 1–32), a DNA-binding domain with POU-like and homeodomain-like motifs (amino acids 150–280), and a COOH-terminal transactivation domain (amino acids 281–631). Because the dimerization domain is intact in many of the mutant forms of HNF-1α found in MODY subjects, these mutant proteins may impair pancreatic β-cell function by forming nonproductive dimers with wild-type protein, thereby inhibiting its activity; that is, they are dominant-negative mutations. This hypothesis was tested by comparing the functional properties of the frameshift mutation P291fsinsC, the most common mutation identified to date in MODY3 patients, and wild-type HNF-1α. P291fsinsC-HNF-1α showed no transcriptional transactivation activity in HeLa cells, which lack endogenous HNF-1α. Overexpression of P291fsinsC-HNF-1α in MIN6 cells, a mouse β-cell line, resulted in an ∼40% inhibition of the endogenous HNF1α activity in a dosage-dependent manner. Furthermore, heterodimer formation between wild-type and P291fsinsC mutant proteins were observed by electrophoretic mobility shift assay. These data suggest that the P291fsinsC mutation in HNF-1α functions as a dominant-negative mutation. However, other mutations, such as those in the promoter region and dimerization domain, may represent loss of function mutations. Thus mutations in the HNF-1α gene may lead to β-cell dysfunction by two different mechanisms.

  • Received February 2, 1998.
  • Revision received April 28, 1998.
  • Accepted April 28, 1998.
  • Copyright © 1998 by the American Diabetes Association

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August 1998, 47(8)
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Mutation P291fsinsC in the Transcription Factor Hepatocyte Nuclear Factor-1α is Dominant Negative
Kazuya Yamagata, Qin Yang, Koji Yamamoto, Hiromi Iwahashi, Jun-ichiro Miyagawa, Kohei Okita, Issei Yoshiuchi, Jun-ichi Miyazaki, Tamio Noguchi, Hiromu Nakajima, Mitsuyoshi Namba, Toshiaki Hanafusa, Yuji Matsuzawa
Diabetes Aug 1998, 47 (8) 1231-1235; DOI: 10.2337/diab.47.8.1231

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Mutation P291fsinsC in the Transcription Factor Hepatocyte Nuclear Factor-1α is Dominant Negative
Kazuya Yamagata, Qin Yang, Koji Yamamoto, Hiromi Iwahashi, Jun-ichiro Miyagawa, Kohei Okita, Issei Yoshiuchi, Jun-ichi Miyazaki, Tamio Noguchi, Hiromu Nakajima, Mitsuyoshi Namba, Toshiaki Hanafusa, Yuji Matsuzawa
Diabetes Aug 1998, 47 (8) 1231-1235; DOI: 10.2337/diab.47.8.1231
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