HNF1A

The HNF1A gene encodes hepatocyte nuclear factor-1 alpha, a transcription factor essential for regulating genes involved in glucose metabolism, lipid balance, insulin secretion, and organ development. 

Mutations in HNF1A are linked to clinical conditions such as Maturity-Onset Diabetes of the Young Type 3 (MODY3) and hepatocellular adenomas, making it a critical focus for genetic diagnosis and targeted therapy.

What is HNF1A (Hepatocyte Nuclear Factor 1 Alpha)?

HNF1A is a gene that encodes a protein called hepatocyte nuclear factor-1 alpha (HNF-1α). 

This protein works as a transcription factor, meaning it binds to DNA and helps control the activity of other genes. 

It plays a key role in regulating glucose and lipid metabolism, inflammation, insulin secretion, and organ development.

HNF1A Gene and Protein

• Located on chromosome 12q24.31
• Encodes the HNF-1α protein (631 amino acids; 67.4 kDa)
• Also known as TCF1, LFB1, or MODY3

Transcription Factor Function

HNF1A has the following functions as a transcription factor:

• Binds DNA as a dimer to regulate target gene expression.
• Controls metabolic genes in the liver (e.g., CYP enzymes), pancreas (insulin production), kidneys, and gut.
• Key to beta cell development and glucose-stimulated insulin secretion.
• May act as a tumor suppressor in liver tissue.

Role in Development and Metabolism

HNF1A plays a vital role in regulating gene expression across multiple organ systems. 

In the liver, it controls genes involved in glucose metabolism, bile acid synthesis, and detoxification pathways. 

In the pancreas, HNF1A is essential for insulin gene expression and supports the growth and function of pancreatic beta cells, which are responsible for insulin production. 

In the kidneys, HNF1A influences renal tubular function, helping to regulate fluid and electrolyte balance. 

In the intestines, it helps control the expression of digestive enzymes and transporter proteins, supporting nutrient absorption and gut health.

Clinical Relevance

The following conditions are associated with mutations in HNF1A mutations:

MODY3 (Maturity-Onset Diabetes of the Young Type 3)

The most well-established clinical consequence of HNF1A mutations is MODY3, the most common form of monogenic diabetes. 

MODY3 typically presents in adolescence or early adulthood and is characterized by autosomal dominant inheritance, mild to moderate hyperglycemia, and preserved insulin production. 

Common symptoms include polyuria, polydipsia, fatigue, weight loss, and recurrent infections. 

Unlike type 1 diabetes, patients with MODY3 usually do not require insulin at diagnosis and often respond well to low-dose sulfonylureas, making early genetic diagnosis highly actionable for guiding treatment and avoiding unnecessary lifelong insulin therapy.

Liver Tumors: Hepatocellular Adenomas (H-HCA)

Another significant association with HNF1A mutations is the development of benign liver tumors, specifically hepatocellular adenomas (H-HCA). These can result from either inherited (germline) or acquired (somatic) mutations in the HNF1A gene. 

HNF1A-mutated adenomas account for approximately 30–40% of all hepatocellular adenomas and are seen more frequently in women. 

Although the tumors are noncancerous, the exact mechanism by which loss of HNF1A function leads to adenoma formation is not fully understood. The gene’s proposed role as a tumor suppressor in liver tissue supports this link.

Rare Endocrine and Metabolic Disorders

In rare cases, mutations in HNF1A have been associated with congenital hyperinsulinism, a condition involving excessive insulin secretion and hypoglycemia in infants. 

Additionally, HNF1A mutations may be linked to atypical or overlapping diabetes syndromes, though these associations are less common and require further research. These rare presentations highlight the gene’s broader role in endocrine regulation and its variable phenotypic expression depending on mutation type and tissue context.

Who Should Get HNF1A Testing?

HNF1A testing may be appropriate in the following settings:

Patients with Suspected MODY3

HNF1A testing is most appropriate for individuals with suspected Maturity-Onset Diabetes of the Young Type 3 (MODY3). This includes people with diabetes diagnosed before age 25, particularly when there is an autosomal dominant inheritance pattern—meaning the condition runs in families across multiple generations. 

Typical features include mild to moderate hyperglycemia, a family history of early-onset diabetes, preserved insulin production (at least initially), and a good clinical response to low-dose sulfonylureas rather than insulin therapy.

Family Members of Patients with MODY3

Testing should also be considered for family members of individuals diagnosed with MODY3, as genetic testing can help identify relatives who have inherited the HNF1A mutation and are at risk of developing diabetes.

Patients with Renal Cysts and Diabetes (RCAD) Syndrome

In rare cases, individuals with Renal Cysts and Diabetes (RCAD) syndrome may have specific mutations in the HNF1A gene. These patients may present with both kidney abnormalities and early-onset diabetes, warranting genetic evaluation.

HNF1A Genetic Testing: Test Procedure and Interpretation

Testing for HNF1A is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for HNF1A genetic testing are considered to be without mutations that can alter the activity of the HNF1A proteins.

What Do Specific HNF1A Mutations Mean?

Identifying a pathogenic HNF1A mutation confirms a genetic diagnosis of MODY3 or, in rare cases, RCAD. These mutations impair the HNF1A protein's ability to bind DNA, regulate downstream gene expression, and support insulin secretion. 

Because MODY3 is inherited in an autosomal dominant pattern, only one copy of the altered gene is needed to cause the condition. 

The specific functional impact of the mutation can vary. Some variants may reduce the protein’s stability or prevent it from entering the nucleus, while others may weaken its ability to bind DNA and activate key metabolic genes.

What Does the Absence of Pathogenic HNF1A Mutations Mean?

A negative test doesn’t rule out MODY from other genes (e.g., GCK, HNF4A).

If clinical suspicion remains high, broader genetic testing is advised.

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