2.1. Maturity-onset Diabetes of the Young

Mutations in the HNF1A gene cause maturity-onset diabetes of the young (MODY), which is a group of conditions characterized by abnormally high blood sugar levels. This form of diabetes usually begins before age 30. HNF1A gene mutations cause the most common type of MODY, called HNF1A-MODY (also known as MODY3). Early symptoms are caused by high blood sugar and include frequent urination (polyuria), excessive thirst (polydipsia), fatigue, blurred vision, weight loss, and recurrent skin infections. Over time, uncontrolled high blood sugar can lead to eye and kidney problems.

HNF1A gene mutations that cause HNF1A-MODY occur in one of the two copies of the gene in each cell. These mutations result in production of an altered HNF-1α protein that is unable to function normally. Some changes prevent the HNF-1α protein from forming dimers; others prevent the protein from entering the nucleus where it interacts with DNA; still others prevent the transcription factor from attaching to DNA to control gene activity. These changes interrupt transcription, altering gene activity in cells. As a result, beta cell development and function are impaired. The cells are less able than normal to produce insulin in response to sugar in the blood, which means blood sugar cannot be controlled. Elevated blood sugar results in the signs and symptoms of MODY.

Rarely, individuals with HNF1A-MODY develop one or more noncancerous (benign) liver tumors called hepatocellular adenomas. In these individuals, a mutation occurs in the second copy of the HNF1A gene in liver cells. This second mutation, called a somatic mutation, is not inherited. It is unclear how the mutations cause liver cells to grow uncontrollably and form tumors.

2.2. Other Disorders

Hepatocellular adenomas also occur in people without HNF1A-MODY (described above). In these individuals, the tumors are associated with somatic mutations in both copies of the HNF1A gene. While rare, hepatocellular adenomas occur in women more frequently than in men, and most affected individuals develop a single tumor. HNF1A-mutated hepatocellular adenomas (also known as H-HCA) account for about 30 to 40 percent of this type of liver tumor. The HNF1A gene mutations that cause these tumors severely reduce or eliminate the function of the HNF-1α protein in affected liver cells. It is unclear how loss of HNF-1α function causes cells to grow uncontrollably and form tumors.