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MODY associated with two novel hepatocyte nuclear factor-1alpha loss-of-function mutations (P112L and Q466X)

L Bjørkhaug1, H Ye, Y Horikawa

  • 1Center for Medical Genetics and Molecular Medicine, University of Bergen, Bergen, N-5021, Norway.

Biochemical and Biophysical Research Communications
|February 13, 2001
PubMed

Insights

Two novel mutations in the hepatocyte nuclear factor (HNF)-1alpha gene, P112L and Q466X, were identified in Norwegian patients with Maturity-onset diabetes of the young (MODY). These mutations impair pancreatic beta-cell function through loss-of-function mechanisms.

Area of Science:

  • Genetics
  • Molecular Biology
  • Endocrinology

Background:

  • Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of diabetes.
  • MODY type 3 is specifically linked to mutations in the hepatocyte nuclear factor (HNF)-1alpha gene.
  • Understanding the molecular basis of HNF-1alpha mutations is crucial for diagnosing and managing MODY.

Purpose of the Study:

  • To identify and characterize novel mutations in the HNF-1alpha gene in Norwegian MODY patients.
  • To elucidate the molecular mechanisms by which these mutations lead to pancreatic beta-cell dysfunction.
  • To investigate the impact of mutations on DNA binding, transcriptional activation, and subcellular localization of HNF-1alpha.

Main Methods:

  • Screening of Norwegian patients for suspected MODY.
  • Identification of two novel HNF-1alpha mutations: P112L and Q466X.
  • Analysis of DNA binding, transcriptional activation, and subcellular localization of mutant HNF-1alpha proteins compared to wild type.

Main Results:

  • P112L mutation showed reduced DNA binding and transcriptional activation.
  • Q466X mutation exhibited reduced transactivation and incomplete nuclear localization.
  • Neither mutation demonstrated a dominant-negative effect when coexpressed with wild-type HNF-1alpha.

Conclusions:

  • Both P112L and Q466X mutations impair HNF-1alpha function through loss-of-function mechanisms.
  • P112L affects DNA binding and transactivation, while Q466X impacts transactivation and nuclear targeting.
  • These findings contribute to understanding the molecular pathology of MODY type 3 and the role of HNF-1alpha.

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