HNF4AMODY1

HNF4A, or hepatocyte nuclear factor 4 alpha, is a nuclear transcription factor of the nuclear receptor family. It is expressed in tissues including the liver and pancreatic beta cells, where it regulates genes involved in glucose and lipid metabolism and supports normal beta-cell development and function.

Mutations in HNF4A cause MODY type 1 (MODY1), a dominantly inherited form of monogenic diabetes. MODY1 results from haploinsufficiency or altered transcriptional control, leading to progressive dysfunction of insulin-secreting beta cells and early-onset hyperglycemia, typically presenting before 25 years of age.

Clinical features of HNF4A-MODY often include a strong family history consistent with autosomal dominant transmission. In addition to diabetes diagnosed in adolescence or early adulthood, some infants born to carrier mothers exhibit neonatal macrosomia and transient neonatal hypoglycemia linked to altered fetal insulin regulation, though these neonatal features are not universal.

Diagnosis relies on genetic testing for HNF4A variants in individuals with suspected MODY—characterized by non-autoimmune, relatively non-obese early-onset diabetes with a positive family history. Autoantibody-negative status helps distinguish MODY from type 1 diabetes, while distinguishing MODY1 from other MODY types may guide management.

Treatment and prognosis vary by individual. Many people with HNF4A-MODY respond well to low-dose sulfonylureas, with some maintaining good glycemic control without insulin; others may require insulin therapy over time. Lifelong monitoring of glycemic control and screening for diabetes-related complications remain important.