Hepatocyte nuclear factor-1 alpha gene mutations and diabetes in Norway

Area of Science:

• Genetics
• Endocrinology
• Molecular Biology

Background:

• Maturity-onset diabetes of the young (MODY) type 3 is caused by mutations in the hepatocyte nuclear factor (HNF)-1 alpha gene.
• Estimating the prevalence of MODY3 in Norwegian diabetic pedigrees is crucial for understanding genetic contributions to diabetes.

Purpose of the Study:

• To determine the prevalence of HNF-1 alpha mutations in Norwegian diabetic families.
• To identify novel HNF-1 alpha mutations associated with MODY3.
• To investigate the functional consequences of identified HNF-1 alpha mutations on protein activity and cellular localization.

Main Methods:

• Screening of 130 Norwegian diabetic pedigrees (42 clinical MODY, 75 suspected MODY, 13 multiplex type 1 diabetes) for HNF-1 alpha mutations.
• Identification and characterization of 18 different HNF-1 alpha mutations, including eight novel ones.
• Functional analysis of 13 HNF-1 alpha mutations to assess DNA binding, nuclear translocation, and transcriptional activation.

Main Results:

• HNF-1 alpha mutations were detected in 22 of 42 clinical MODY families, 15 of 75 suspected MODY families, and one of 13 multiplex type 1 diabetes families.
• Eight novel HNF-1 alpha mutations were identified among the 18 different mutations found.
• Functional studies revealed that several HNF-1 alpha mutants exhibited impaired DNA binding, defective nuclear translocation, and reduced transcriptional activation, indicating loss-of-function mechanisms.

Conclusions:

• Approximately half of Norwegian families with clinical MODY harbor HNF-1 alpha mutations, confirming its significant role in MODY3.
• Identified HNF-1 alpha mutations, including novel ones, provide further insight into the genetic landscape of MODY3.
• Loss-of-function mechanisms, such as impaired DNA binding, nuclear translocation, and transcriptional activation, underlie beta-cell dysfunction in MODY3.