Genetic Features Of Hemochromatosis

Some features of hemochromatosis are displayed in Table 1.[1-3] Hemochromatosis is linked to human leukocyte antigen (HLA) class I genes within the major histocompatibility complex (MHC) region on Ch6p.[1] Mutations in a nonclassical MHC class I gene (HFE), which maps ~4 Mb telomeric to HLA-A at 6p21.3, account for most cases in Caucasians[4] (Table 2). ''Classic'' hemochromatosis is associated with homozy-

gosity for the HFE C282Y mutation. C282Y often lies within an ancestral HLA haplotype A*03-B*07.[1,6] This haplotype is the predominant hemochromatosis-associated haplotype in northwestern European countries.[6] This is attributed to the origin of C282Y on an A*03-B*07 haplotype in northwestern Europe and its early dissemination by Vikings.[6] Modification of the ancestral chromosome by recombination and admixture as a result of geographic migration explains the occurrence of chromosomes bearing C282Y in association with different HLA haplotypes.[6] Thus some nonancestral haplotypes also occur with significantly increased frequencies in hemochromatosis patients in various countries in Europe and in descendants of Europeans.[6]

C282Y and H63D, the most common HFE mutations detected in Caucasians, occur with frequencies of 0.010.14 and 0.05-0.22, respectively.1-7-1 Frequencies of these mutations vary among racial, ethnic, or national groups, and are positively correlated with the prevalence of hemochromatosis.[7] In various Caucasian populations, 60-100% of hemochromatosis cases are attributable to homozygosity for C282Y.[4,8] Some patients are compound heterozygotes for C282Y and H63D, or are H63D homozygotes.[4,8] Other persons with a hemochromatosis phenotype have ''atypical'' HFE genotypes, i.e., are heterozygous for C282Y or H63D, have uncommon HFE mutations, or do not have a detectable mutation in HFE coding regions (Table 2).[4,8,9] Differences in case ascertainment criteria could partly explain dissimilarities in the geographic distribution of hemochromatosis patients with ''atypical'' HFE genotypes.[8,9] Missense mutations in other genes that control iron absorption could also account for hemochromatosis phenotypes in some cases.

The severity of iron overload in Caucasians with hemochromatosis is variable, and is correlated with the particular HFE genotype; for example, persons with the genotype C282Y/C282Y usually have more stored iron at diagnosis than persons with the genotypes C282Y/H63D or H63D/H63D.[8] Persons who inherit C282Y on the ancestral haplotype characterized by HLA-A*03,-B*07 may have more severe iron overload, on the average, than those who lack this haplotype.[10] Some investigators have suggested that ''mutations at a second HLA-linked locus,

Clinical feature

Caucasians of European descent


Usually elevated

Often elevated

Excess iron is deposited in almost all organs and tissues in severe cases, especially liver

Primarily parenchymal cells

Hepatic cirrhosis, primary liver cancer, diabetes mellitus, hypogonadotrophic hypogonadism, arthropathy, cardiomyopathy, hyperpigmentation, abnormalities of ascorbic acid (vitamin C) metabolism Autosomal recessive Mutations in HFE Phlebotomy

Table 1 Features of hemochromatosis Variable

Affected populations Prevalence in populations Prevalence in liver biopsy specimens Serum transferrin saturation with iron Serum ferritin concentration Primary target organs of iron overload

Pattern of iron deposition Complications of iron overload

Pattern of inheritance Associated genes

Prevention or treatment of iron overload Source: From Ref. [3].

Table 2 HFE mutations associated with hemochromatosis


Nucleotide change

Mutation designation


- 7 T ! C


Exon 2


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