Clinical and pathologic findings in hemochromatosis type 3 due to a novel mutation in transferrin receptor 2 gene

Background & Aims: Although most patients with hereditary hemochromatosis are homozygous for a single mutation of the HFE gene on chromosome 6p, accumulating evidence indicates that the disease is genetically heterogeneous. Type 3 hemochromatosis, recently described in 4 families, is linked to mutations of the gene encoding transferrin receptor 2 on chromosome 7q22. Here we report data from a family carrying a new mutation of the transferrin receptor 2 gene. Methods: tailed clinical and histopathologic documentation was available for most family members. The entire coding sequence and exon/intron boundaries of the transferrin receptor 2 gene were analyzed by direct sequencing. Results: A 12-nucleotide deletion in exon 16, causing the loss of 4 amino acids (AVAQ 594-597 del), was detected at the homozygous state in the 3 patients with histologically proven iron overload. The deletion segregated with the disease within the family and was not found in 100 healthy controls. Some clinical and pathologic characteristics, such as low penetrance in the premenopausal woman, and early iron deposition in periportal hepatocytes resembled those of classic, HFE-related hemochromatosis. Conclusions: Our data support the role of the transferrin receptor 2 gene in hemochromatosis type 3 as well as its critical involvement in the maintenance of Iron homeostasis In humans.