Which gene mutation is responsible for the majority of cases of hereditary hemochromatosis?

Explanation

## HFE Gene and Hereditary Hemochromatosis **Key Point:** The HFE gene encodes a protein that regulates hepcidin expression, the master iron-regulatory hormone. Mutations in HFE account for approximately 80–90% of hereditary hemochromatosis cases in populations of Northern European descent. ### HFE Gene Mutations **High-Yield:** The most common mutation is **C282Y** (homozygous), which results in a cysteine-to-tyrosine substitution at codon 282. This disrupts the interaction between HFE and transferrin receptor 1 (TfR1), leading to: - Reduced hepcidin production - Increased intestinal iron absorption - Progressive iron overload in liver, heart, pancreas, and joints ### Clinical Presentation Timeline | Feature | Typical Age of Onset | Gender Bias | |---------|---------------------|-------------| | Elevated ferritin | 30–40 years | Males > Females | | Cirrhosis | 40–50 years | Males predominantly | | Diabetes mellitus | 40–60 years | Males > Females | | Arthropathy | 30–50 years | Males and females | **Clinical Pearl:** Heterozygous C282Y carriers (C282Y/wild-type) rarely develop clinical hemochromatosis unless additional iron-loading conditions (e.g., chronic hepatitis C, alcoholism) are present. ### Other Gene Mutations (Non-HFE Hemochromatosis) These account for 10–20% of hereditary cases: - **HAMP gene** (juvenile hemochromatosis; severe, early-onset) - **TFR2 gene** (hemochromatosis type 3) - **SLC40A1 gene** (ferroportin disease; iron retention in macrophages rather than parenchymal cells) **Mnemonic:** **HFE-C282Y = 80–90% of cases** — this is the single most testable fact in hemochromatosis genetics.