The main driver mutation for hereditary hemochromatosis is:

The main driver mutation for hereditary hemochromatosis is:

• A. H63D
• B. C282Y
• C. S65C
• D. G711R

Answer: (B)

Hereditary hemochromatosis is most commonly driven by a mutation in the HFE gene, specifically C282Y. This change disrupts the HFE protein’s ability to regulate iron sensing on the cell surface, leading to inappropriately low hepcidin levels and increased intestinal iron absorption with iron overload over time. The C282Y substitution, which replaces cysteine with tyrosine at position 282, impairs proper folding and surface expression of HFE, diminishing its regulatory effect on iron uptake. This mutation is especially prevalent in individuals of Northern European ancestry and is most penetrant when present in two copies (homozygous). Other HFE variants like H63D and S65C exist but contribute less to the classic, high-penetrance phenotype, and G711R is not a common driver of hereditary hemochromatosis.

Hereditary hemochromatosis is most commonly driven by a mutation in the HFE gene, specifically C282Y. This change disrupts the HFE protein’s ability to regulate iron sensing on the cell surface, leading to inappropriately low hepcidin levels and increased intestinal iron absorption with iron overload over time. The C282Y substitution, which replaces cysteine with tyrosine at position 282, impairs proper folding and surface expression of HFE, diminishing its regulatory effect on iron uptake. This mutation is especially prevalent in individuals of Northern European ancestry and is most penetrant when present in two copies (homozygous). Other HFE variants like H63D and S65C exist but contribute less to the classic, high-penetrance phenotype, and G711R is not a common driver of hereditary hemochromatosis.