Alternative titles; symbols
SNOMEDCT: 1186847009, 35400008, 399053004, 399170009; ICD10CM: E83.110; ICD9CM: 275.01; ORPHA: 465508; DO: 0111029;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p22.2 | Hemochromatosis, type 1 | 235200 | Autosomal recessive | 3 | HFE | 613609 |
| 20p12.3 | {HFE hemochromatosis, modifier of} | 235200 | Autosomal recessive | 3 | BMP2 | 112261 |
A number sign (#) is used with this entry because hemochromatosis type 1 (HFE1) is caused by homozygous or compound heterozygous mutation in the HFE gene (613609) on chromosome 6p22.
Hereditary hemochromatosis is an autosomal recessive disorder of iron metabolism wherein the body accumulates excess iron (summary by Feder et al., 1996). Excess iron is deposited in a variety of organs leading to their failure, and resulting in serious illnesses including cirrhosis, hepatomas, diabetes, cardiomyopathy, arthritis, and hypogonadotropic hypogonadism. Severe effects of the disease usually do not appear until after decades of progressive iron loading. Removal of excess iron by therapeutic phlebotomy decreases morbidity and mortality if instituted early in the course of the disease. Classic hemochromatosis (HFE) is most often caused by mutation in a gene designated HFE on chromosome 6p21.3.
Adams and Barton (2007) reviewed the clinical features, pathophysiology, and management of hemochromatosis.
Genetic Heterogeneity of Hemochromatosis
At least 4 additional iron overload disorders labeled hemochromatosis have been identified on the basis of clinical, biochemical, and genetic characteristics. Juvenile hemochromatosis, or hemochromatosis type 2 (HFE2), is autosomal recessive and is divided into 2 forms: HFE2A (602390), caused by mutation in the HJV gene (608374) on chromosome 1q21, and HFE2B (613313), caused by mutation in the HAMP gene (606464) on chromosome 19q13. Hemochromatosis type 3 (HFE3; 604250), an autosomal recessive disorder, is caused by mutation in the TFR2 gene (604720) on chromosome 7q22. Hemochromatosis type 4 (HFE4; 606069), an autosomal dominant disorder, is caused by mutation in the SLC40A1 gene (604653) on chromosome 2q32. Hemochromatosis type 5 (HFE5; 615517) is caused by mutation in the FTH1 gene (134770) on chromosome 11q12.
Muir et al. (1984) recognized 4 different types of hereditary hemochromatosis which 'bred true' in families, suggesting that more than one genetic lesion in iron metabolism can lead to hereditary hemochromatosis. Group I was termed the classic form with elevated transferrin (190000) saturation, serum ferritin levels, and liver iron content; group II was characterized by severe iron overload and accelerated disease manifesting at an early age; group III was characterized by elevated total body iron stores, normal transferrin saturation and serum ferritin levels; and group IV was characterized by markedly elevated findings on serum biochemical tests, i.e., transferrin saturation and serum ferritin, with minimal elevation in total body iron stores. Milman et al. (1992) found no relationship between genetic subtypes of transferrin and the expression of disease in hemochromatosis patients.
Edwards et al. (1980) identified 35 hemochromatosis homozygotes through pedigree studies, using the close linkage to HLA-A (142800) in the identification. Thirteen were asymptomatic. Arthropathy was present in 20, hepatomegaly in 19, transaminasemia in 16, skin pigmentation in 15, splenomegaly in 14, cirrhosis in 14, hypogonadism in 6, and diabetes in 2. None had congestive heart failure. Only 1 had the triad of hepatomegaly, hyperpigmentation, and diabetes. Serum iron was increased in 30 of 35, transferrin saturation was increased in all 35, serum ferritin in 23 of 32, urinary iron excretion after deferoxamine in 28 of 33, hepatic parenchymal cell stainable iron in 32 of 33, and hepatic iron in 27 of 27. Iron loading was 2.7 times greater in men than in women. No female had hepatic cirrhosis.
By studying 1,058 individuals who were heterozygous for the HLA-linked hemochromatosis mutation, Bulaj et al. (1996) found that the mean serum iron concentrations and transferrin-saturation values were higher in heterozygotes than in normal subjects and did not increase with age. Initial transferrin-saturation levels exceeding the threshold associated with the homozygous genotype were found in 4% of males and 8% of female heterozygotes. The geometric mean serum ferritin concentration was higher in heterozygotes than in normal subjects and increased with age. Higher-than-normal values were found in 20% of males and 8% of female heterozygotes. The clinical and biochemical expression of hemochromatosis was more marked in heterozygotes with paternally transmitted mutations than in those with maternally transmitted mutations. Liver biopsy abnormalities were generally associated with alcohol abuse, hepatitis, or porphyria cutanea tarda. Bulaj et al. (1996) concluded that complications due to iron overload alone in hemochromatosis heterozygotes are 'extremely rare.' This was the first description of parent-of-origin effects in hemochromatosis.
Escobar et al. (1987) established the diagnosis of hemochromatosis in a 7-year-old boy and his 29-month-old brother. These were said to be the youngest children with primary hemochromatosis reported to that time. They were members of a family in which 3 generations had affected individuals. Data from the literature on values of serum iron, serum ferritin, transferrin saturation, and hepatic iron were reviewed. Kaikov et al. (1992) described hemochromatosis in asymptomatic sibs in whom the diagnosis was made after an unexpected finding of elevated serum iron concentrations. The sibs were 7, 6, and 4 years of age. Elevated red cell mean corpuscular volume (MCV) was elevated in all 3, at 90 to 92 fL. In their review of the literature, they found 16 cases of symptomatic homozygous children at ages ranging from 4 to 19 years at the time of diagnosis. They suggested that normalization of the MCV may be an indirect index of adequate phlebotomy. The cases of Escobar et al. (1987) and Kaikov et al. (1992) may have been juvenile hemochromatosis (602390).
Perez Roldan et al. (1998) described acute liver failure after iron supplementation in a 29-year-old woman with unrecognized hemochromatosis.
Roy and Andrews (2001) reviewed disorders of iron metabolism, with emphasis on aberrations in hemochromatosis, Friedreich ataxia (FRDA; 229300), aceruloplasminemia (604290), and other inherited disorders.
McDermott and Walsh (2005) assessed the prevalence of hypogonadism in a large group of patients with hemochromatosis diagnosed in a single center over a 20-year period. Abnormally low plasma testosterone levels, with low luteinizing hormone (LH; see 152780) and follicle-stimulating hormone (FSH; see 136530) levels, were found in 9 of 141 (6.4%) male patients tested. Eight of nine (89%) had associated hepatic cirrhosis; 3 of 9 (33%) had diabetes. Inappropriately low LH and FSH levels were found in 2 of 38 females (5.2%) in whom the pituitary-gonadal axis could be assessed. McDermott and Walsh (2005) concluded that patients with lesser degrees of hepatic siderosis at diagnosis are unlikely to develop hypogonadism.
Liver Cirrhosis and Liver Cancer
Deugnier et al. (1993) analyzed the occurrence of primary liver cancer in hemochromatosis; there was 1 instance of cholangiocarcinoma and 53 instances of hepatocellular carcinoma (HCC; 114550). Of the 54 patients, 32 were untreated and 22 had been 'de-ironed.' Three of the patients had hepatocellular carcinoma in noncirrhotic but only fibrotic liver. Chronic alcoholism and tobacco smoking was higher in patients with hepatocellular carcinoma than in matched hemochromatosis patients without carcinoma.
A common manifestation of tissue damage caused by iron accumulation in hereditary hemochromatosis is hepatic cirrhosis that may lead to hepatocellular carcinoma. Willis et al. (2000) determined the risk of developing such disease manifestations in individuals with HFE mutations in Norfolk, UK. The frequency of mutant HFE alleles in archived liver tissue blocks from patients with cirrhosis or liver cancer was compared with that in 1,000 control blood samples. This control group was derived from a number of sources; no sample was from an individual with diagnosed HH. Of 34 cases of liver cancer, 3 (8.8%) were homozygous for the C282Y (613609.0001) mutation (2 hepatocellular carcinomas, 1 undifferentiated liver carcinoma). None of these patients had been given a diagnosis of HH prior to the diagnosis of liver cancer. None were C282Y/H63D (613609.0002) compound heterozygotes. Five of 190 cirrhosis samples (2.6%) were homozygous for C282Y; 4 of these patients had been given a clinical diagnosis of HH at the time of biopsy, and the remaining case fell also into the liver cancer group. Six cirrhosis samples were from C282Y/H63D compound heterozygotes; none had been given a clinical diagnosis of HH. The frequency of C282Y homozygotes in the control group was 1 in 230, and of C282Y/H63D compound heterozygotes was 1 in 108. HFE mutations were significantly more common in disease than in control specimens. Willis et al. (2000) calculated that, in their population, 2.7% of C282Y homozygotes and 1% of C282Y/H63D compound heterozygotes develop liver disease at some point in their lives.
Both Wilson disease (WND; 277900) and hemochromatosis, characterized by excess hepatic deposition of iron and copper, respectively, produce oxidative stress and increase the risk of liver cancer. Because the frequency of p53 mutated alleles (191170) in nontumorous human tissue may be a biomarker of oxyradical damage and identify individuals at increased cancer risk, Hussain et al. (2000) determined the frequency of p53 mutated alleles in nontumorous liver tissue from WND and hemochromatosis patients. When compared with the liver samples from normal controls, higher frequencies of G:C to T:A transversions at codon 249, and C:G to A:T transversions and C:G to T:A transitions at codon 250 were found in liver tissue from WND cases, and a higher frequency of G:C to T:A transversions at codon 249 was also found in liver tissue from hemochromatosis cases. Sixty percent of WND and 28% of hemochromatosis cases also showed a higher expression of inducible nitric oxide synthase in the liver, which suggested nitric oxide as a source of increased oxidative stress. The results were consistent with the hypothesis that the generation of oxygen/nitrogen species and unsaturated aldehydes from iron and copper overload in hemochromatosis and WND causes mutation in the p53 tumor suppressor gene.
Chromium, an essential trace mineral required for normal insulin function, is transported bound to transferrin and competes with iron for that binding. Sargent et al. (1979) found that less chromium is retained in patients with hemochromatosis than in controls, and suggested that the diabetes of hemochromatosis may be due in part to chromium deficiency.
Murphy (1987) noted that a considerable proportion of the patients who develop Vibrio vulnificus septicemia are persons with hemochromatosis. This organism thrives in an environment with abundant iron. It occurs naturally in many warm coastal waters and sometimes contaminates shellfish harvested from these areas. The organism can cause infection when ingested in raw or improperly cooked contaminated shellfish or when introduced into the open wounds of persons who handle contaminated seafood or bathe in contaminated waters. Bacteremia due to V. vulnificus in patients with hemochromatosis may be related to the availability of iron for microbial metabolism or to the presence of hepatic cirrhosis (Bullen et al., 1991) and is often fatal.
Diamond et al. (1989) studied the prevalence and pathogenesis of osteopenia in 22 men with hemochromatosis. They concluded that a significant decrease in bone density is observed in this condition, particularly when hypogonadism is present. They speculated that low serum free-testosterone concentrations, rather than calciotrophic hormones, determine bone mass in this disorder.
Barton et al. (1994) demonstrated that hemochromatosis homozygotes and, to a lesser extent, heterozygotes, both male and female, have increased blood levels of lead. In contrast, mean blood lead of subjects with transfusion-induced iron overload did not differ significantly from that of normal controls. The findings in homozygotes could not be related to age, presence or absence of iron loading, or the extent of therapeutic phlebotomy. Increased absorption of iron and cobalt, which may have the same absorptive pathway, had previously been documented in homozygotes; the new findings were interpreted as indicating increased absorption of lead as well. The findings suggested that patients with hemochromatosis, like children with iron deficiency, are more susceptible to lead poisoning.
Anand et al. (1983) and Eriksson et al. (1986) described cases suggesting a possible relationship between alpha-1-antitrypsin deficiency (613490) and hemochromatosis. In a series of 15 patients referred to a liver transplantation center in the U.S., Rabinovitz et al. (1992) found a significant correlation between heterozygous PiZ (107400.0011) alpha-1-antitrypsin deficiency and hemochromatosis. Other studies, however, failed to show a relationship between the 2 inborn errors of metabolism. To investigate the matter further, Elzouki et al. (1995) used a monoclonal antibody against the PiZ variant of AAT in 67 consecutive patients with genetic hemochromatosis seen in 2 Swedish hospitals. In 3 of the patients with hemochromatosis, homozygosity for the PiZ variant was found. Liver biopsy was performed in 65 of the 67 patients; 2 of the 3 PiZ homozygotes were found to have cirrhosis, compared to 10% (6 of 59) of the noncarriers of the PiZ variant. None of the homozygous or heterozygous AAT-deficient patients had developed hepatocellular carcinoma compared with 2 of 59 of the non-PiZ gene carriers. Severe emphysema developed in 2 of the patients with the homozygous phenotype. Elzouki et al. (1995) concluded that the data suggested that the presence of the PiZ allele in double dose when associated with genetic hemochromatosis contributes to the earlier onset of cirrhosis, although it may not increase the risk of hepatocellular carcinoma.
Grove et al. (1998) examined the hypothesis that mutations in the HFE gene determine hepatic iron status in alcoholics and predispose to advanced alcoholic liver disease. The sample population was derived from the northeast of England and consisted of 257 individuals with alcoholic liver disease and 117 controls from the local population. No significant excess of C282Y (613609.0001) or H63D (613609.0002) alleles was demonstrated in alcoholics with advanced liver disease compared to those with no liver disease. There was no difference in age at biopsy or presentation. No difference in allele distribution was noted between alcoholics and controls. No relationship between allele frequency and histologic evidence of iron overload was noted. The authors commented that HFE mutations did not predispose to advanced liver disease in alcoholics.
Because ceruloplasmin (CP; 117700) seems to be involved in iron mobilization, Cairo et al. (2001) measured serum CP levels in 35 patients with hereditary hemochromatosis, 12 patients with acquired iron overload, and 36 healthy subjects. Ceruloplasmin was lower in HH patients than in controls; no difference was found between untreated HH patients and those on a phlebotomy program and between HH patients carrying the normal and mutated alleles of the HFE gene. CP levels in patients with acquired iron overload were significantly higher than in HH patients and similar to those of controls. No differences in albumin, alpha-1-acid glycoprotein, or copper serum levels were observed in the 3 groups.
Cippa and Krayenbuehl (2013) hypothesized that sustained enhanced iron absorption in patients with HFE hemochromatosis may have a beneficial effect on growth. They assessed the height in a cohort of 176 patients with HFE hemochromatosis at the University Hospital Zurich. Homozygous C282Y (613609.0001) mutations were found in 93% of patients, whereas compound heterozygosity for H63D (613609.0002) and C282Y mutations was found in 7%. Height in patients with hemochromatosis was compared with that in an age- and sex-matched Swiss reference population, with the use of data reported in the registry of military conscription and by the Swiss Federal Statistical Office. The mean height in men with hemochromatosis (120) was 178.2 cm, versus 173.9 cm in controls (458,322), a difference of 4.3 cm (95% CI, 3.0 to 5.5; p less than 0.001). The mean height in women with hemochromatosis (56) was 167.1 cm, versus 163.8 cm in controls (10,260), a difference of 3.3 cm (95% CI, 1.3 to 5.3; p less than 0.001). Cippa and Krayenbuehl (2013) speculated that patients with HFE hemochromatosis may benefit in their first 2 decades from constantly enhanced iron absorption, providing a steadily sufficient supply of iron during physical development.
Debre et al. (1958) concluded that the biochemical defect of idiopathic hemochromatosis is present in heterozygotes and that whether the disease develops is dependent on other influences on iron metabolism. They suggested that juvenile hemochromatosis resulting from consanguineous marriages may represent the homozygous state of the gene.
Bothwell et al. (1959), Debre et al. (1958), and several others concluded that 1 form of hemochromatosis is inherited as an autosomal dominant disorder with incomplete penetrance in females because of loss of blood in menstruation and pregnancy. Saddi and Feingold (1974) reported a study of 96 pedigrees which, they concluded, supported autosomal recessive inheritance. Consanguinity was increased among the parents. No parent or offspring was affected. Segregation analysis was consistent with autosomal recessive inheritance if reduced penetrance in females was assumed.
Simon et al. (1977) concluded that idiopathic hemochromatosis is recessive, although polygenic (probably oligogenic) inheritance could not be excluded.
Bassett et al. (1982) provided evidence that clarified some of the previous confusion of whether hemochromatosis is a recessive or a dominant. They observed 5 families with hemochromatosis in 2 successive generations. HLA typing of the subjects indicated that a homozygous-heterozygous mating almost certainly had occurred in 4 of the 5 families, resulting in homozygous offspring. Powell et al. (1987) restudied a family reported by Bassett et al. (1982) in which 2 children apparently homozygous for hemochromatosis did not manifest overt disease; alternative explanations such as dominant inheritance were postulated. Subsequent studies provided the correct explanation (pseudodominant inheritance) and added further evidence for the tight linkage of HFE to HLA-A.
Borecki et al. (1989) performed a segregation analysis on 147 HH pedigrees from Brittany, France, indexed by the measurement of latent capacity of transferrin. No evidence for heterozygous expression was observed, either in the biochemical domain of latent capacity of transferrin, or in increased liability to overt disease. The analysis allowed clear resolution of the recessive single gene inheritance pattern in these families. Borecki et al. (1990) concluded that the hemochromatosis gene is completely recessive with respect to both clinical manifestations and serum iron abnormalities, with significant differences in expression by sex. Clinical manifestations were present in all male homozygotes, suggesting that the recessive hemochromatosis genotype is fully penetrant at all ages in males. This was not the case for younger females, however.
Simon et al. (1976) found HLA-A3 in 78.4% of hemochromatosis patients and 27% of controls; HLA-B14 was found in 25.5% of cases and 3.4% of controls. Among sibs with hemochromatosis, Simon et al. (1977) found a highly significant association between hemochromatosis and possession of the same 2 haplotypes. For 6 families a lod score of 2.239 at a recombination fraction of 0.005 supported linkage of HLA and hemochromatosis.
Stevens et al. (1977) concluded that a gene for hemochromatosis may be on chromosome 6 close to the HLA-A locus in linkage disequilibrium with high frequency of A3 in patients with hemochromatosis.
Cartwright et al. (1978) obtained lod scores well above the 3.0 for the HLA-hemochromatosis linkage. That the high lod score is not an artifact due to A3, B7 and B14 associations was supported by the finding of a lod score of 4.14 at theta 0.00 in 5 pedigrees in which these antigens were not present in the probands (Dadone et al., 1982). Skolnick (1983) contended that linkage disequilibrium cannot explain the HLA-hemochromatosis association because the association is with a haplotype, either A3-B7 or A3-B14.
Edwards et al. (1985, 1986) presented the first known example of recombination between the HLA-A and hemochromatosis loci and proposed that the (or at least a) hemochromatosis locus lies between the HLA-A and HLA-B loci.
David et al. (1986, 1987) studied an exceptional recombinant family with 3 HLA-identical sibs: 1 had hemochromatosis, whereas the other 2 were free of any clinical or biologic signs of the disease. The study of restriction patterns using 2 MHC class I probes showed 2 differences between the proband and his sibs which were attributed to an unbalanced crossover or a genetic conversion. The absence of a 7.7-kb HindIII fragment in the proband suggested that this segment is the location of at least part of the hemochromatosis gene. Furthermore, it appeared that the hemochromatosis gene lies telomeric to the HLA-A locus. Lucotte and Coulondre (1986) found that a specific PvuII restriction fragment correlates absolutely with the HLA-A3 serologic allele and with the hemochromatosis allele.
Using pulsed field gel electrophoresis in conjunction with probes that map within, or in the vicinity of, the HLA class I region, Lord et al. (1990) did not detect any disease-specific differences in affected members of 3 HH pedigrees or in 6 unrelated patients with the disorder. The authors concluded that the lesion responsible for HH lies beyond the resolution of this technique and does not involve large structural deletions or extensive rearrangements.
Boretto et al. (1992) reported linkage studies with restriction polymorphisms which were consistent with location of the hemochromatosis locus either less than 100 kb centromeric to the HLA-A locus or on its telomeric side.
Jazwinska et al. (1993) found a maximum lod score of 9.90 at theta = 0.0 for HLA-A and 8.26 at theta = 0.0 for a microsatellite marker at D6S105. No recombination was observed with either marker. Other markers were separated from the hemochromatosis locus by recombination, thereby defining the centromeric and telomeric limits for the HFE gene as HLA-B and D6S109, respectively. A multipoint map indicated that hemochromatosis locus is located in a region less than 1 cM proximal to HLA-A and less than 1 cM telomeric of HLA-A.
In a single family with hemochromatosis, Calandro et al. (1995) identified 2 recombinant individuals confirmed by analysis of 16 polymorphic markers located near HLA-A and D6S105. One of the recombinants provided evidence that the HH gene is telomeric to the 5-prime end of the HLA-F locus. The HLA-F locus was placed approximately 0.027 cM distal to HLA-A, which in turn was 0.01 cM distal of HLA-B. Raha-Chowdhury et al. (1996) showed that a highly polymorphic polypurine tract in the 5-prime untranslated region of HLA-F is as strongly associated with hemochromatosis as HLA-A3 or D6S105-8. The observed frequency of heterozygosity at the HLA-F polymorphism was 95% and the locus was found to be informative in pedigrees that are not informative at HLA-A and D6S105.
By fluorescence in situ hybridization analysis, Hashimoto et al. (1995) mapped the HFE gene to chromosome 6p22.
Edwards et al. (1981) suggested that 2 families reported by Wands et al. (1976) and Rowe et al. (1977) may have had a rare distinct form of hemochromatosis. In these families, neither serum ferritin concentration nor transferrin saturation was a reliable indicator of hepatic siderosis and fibrosis. Hepatic fibrosis was observed in some individuals with a very modest increase in hepatic iron and in a few individuals with normal hepatic iron content. The disorder appeared to be transmitted as an autosomal dominant. No HLA data were reported in these families.
In Australia, Jazwinska et al. (1996) found that all patients of northern European origin with hemochromatosis were homozygous for the cys282-to-tyr mutation (C282Y; 613609.0001). The frequency was greater than 90% in Brittany (Jouanolle et al., 1996). However, in Italy, Carella et al. (1997) performed mutation analysis on the HFE gene in patients from families with the 6p-linked disease but without the C282Y mutation and failed to find nucleotide abnormalities in coding sequences and intron/exon boundaries that could account for the disorder. The negative findings of RNA-SSCP were supported by the absence of mutations in the HFE gene by direct sequencing. Major deletions or rearrangements of the gene were excluded by Southern blotting. Carella et al. (1997) concluded that hemochromatosis in Italy appears to be more heterogeneous than reported in northern Europe, and suggested abnormalities in unexplored portions of introns, RNA untranslated regions, regulatory elements, or another tightly linked locus as alternative possibilities for the cause of the disorder. Studies by Carella et al. (1997) and Piperno et al. (1998) indicated that only 64% of patients with hemochromatosis in Italy were homozygous for the C282Y mutation.
In commenting on the report of Carella et al. (1997), Beutler (1997) pointed to the 0.01 gene frequency in the Italian population, which is considerably lower than in persons of European ancestry who have been studied in the United States and in northern Europe. In agreement with the data from this southern European population, Beutler and Gelbart (1997) found that among nearly 400 Ashkenazi Jews the gene frequency of the C282Y mutation was only 0.013, compared with 0.07 in the non-Jewish American white population. These findings and those of Carella et al. (1997) seem consistent with the putative Celtic origin of the C282Y mutation (Jazwinska et al., 1995).
In patients with hereditary hemochromatosis, Feder et al. (1996) identified 2 mutations in the HFE gene (C282Y; 613609.0001 and 613609.0002). The C282Y mutation was detected in 85% of all HFE chromosomes, indicating that in their population 83% of hemochromatosis cases are related to C282Y homozygosity.
Beutler et al. (1997) pointed out that calreticulin (CALR; 109091), like beta-2-microglobulin (B2M; 109700), associates with class I HLA proteins and appears to be identical to mobilferrin, a putative iron transport protein. Thus these 2 proteins were considered candidates for mutations in patients with hemochromatosis. The investigators sequenced the coding region and parts of introns of the HFE gene (called by them HLA-H), the B2M gene, and the CALR gene in 10, 7, and 5 hemochromatosis patients, respectively, selecting those who were not homozygous for the common C282Y mutation. No additional mutations were found in the HLA-H gene and no disease related mutations in the other 2 genes. The authors noted that the basis for hemochromatosis in more than 10% of European patients and in most Asian patients awaits explanation. Beutler et al. (1997) speculated that the finding of some effects in heterozygotes (Bulaj et al., 1996) and the rarity of mutations other than C282Y and his63 to asp (H63D; 613609.0002) may point to a gain-of-function consequence of these mutations, similar, they suggested, to sickle cell anemia, which is caused by only 1 type of mutation (see 141900.0038) and represents in effect a gain-of-function mutation. The unique mutation causing achondroplasia, gly380 to arg (G380R; 134934.0001), might also be cited.
By sequence analysis of exons 2, 3, 4, and 5, and portions of introns 2, 4, and 5 of the HFE gene, Barton et al. (1999) identified novel mutations in 4 of 20 hemochromatosis probands who lacked C282Y homozygosity, C282Y/H63D compound heterozygosity, or H63D homozygosity. Probands 1 and 2 were heterozygous for the previously undescribed mutations ile105 to thr (I105T; 613609.0009) and gly93 to arg (G93R; 613609.0010). Probands 3 and 4 were heterozygous for the previously described but uncommon HFE mutation ser65 to cys (S65C; 613609.0003). Proband 3 was also heterozygous for C282Y and had porphyria cutanea tarda (see 176100), and proband 4 had hereditary stomatocytosis (185000). Each of these 4 probands had iron overload. In each proband with an uncommon HFE coding region mutation, I105T, G93R, and S65C occurred on separate chromosomes from those with the C282Y or H63D mutations. Neither I105T, G93R, nor S65C occurred as spontaneous mutations in these probands. In 176 normal control subjects, 2 were heterozygous for S65C, but I105T and G93R were not detected.
Griffiths and Cox (2000) reviewed the molecular pathophysiology of iron metabolism.
Pietrangelo (2004) reviewed the various forms of hemochromatosis. In a useful diagram, he illustrated the polygenic nature and phenotypic continuum of hereditary hemochromatosis. The continuum involves age at onset, clinical severity, and contribution of host or environmental factors to expressivity. Intermediate phenotypes can result from combined heterozygous mutations (compound heterozygosity) or homozygous mutations of more than 1 hemochromatosis gene. For instance, the relatively mild phenotype associated with homozygous mutation of HFE can be aggravated and accelerated by a coexisting heterozygous mutation in a gene associated with a juvenile form of the disease, such as HAMP. The latter mutation, combined with a normally silent heterozygous HFE mutation, can also result in unexpected expression of disease.
Lee et al. (2004) identified a patient with adult-onset hemochromatosis who was compound heterozygous for mutations in the HJV gene (G320V, 608374.0001; 608374.0007).
Genetic Modifiers
In patients with 'atypical' hemochromatosis, defined as having a discordant iron phenotype despite having the same HFE genotype, Hofmann et al. (2002) performed mutation analysis of the transferrin receptor-2 gene (TFR2), which is mutated in HFE3. Sib pairs homozygous for HFE C282T had a discordant phenotype in serum transferrin concentration and/or significant differences in liver fibrosis and liver enzyme levels. Also included were individuals who were not homozygous for C282Y, but who had evidence of iron excess. In a pair of brothers homozygous for the C282Y mutation, Hofmann et al. (2002) found a mutation in the TFR2 only in the brother with liver fibrosis, suggesting that TFR2 functions as a modifier for penetrance of the hemochromatosis phenotype when present with homozygosity for C282Y. The screening for mutations in all 18 exons indicated that mutations of the TFR2 gene are rare.
Merryweather-Clarke et al. (2003) described 2 families who exhibited digenic inheritance of hemochromatosis. In family A, the proband had a JH phenotype and was heterozygous for the C282Y mutation in the HFE gene as well as a frameshift mutation in the HAMP gene (606464.0003). The proband's unaffected mother was also heterozygous for the HAMP frameshift mutation, but lacked the HFE C282Y mutation and was heterozygous for the HFE H63D mutation (613609.0002). In family B, there was a correlation between severity of iron overload, heterozygosity for a HAMP G71D mutation (606464.0004), and heterozygosity or homozygosity for the HFE C282Y mutation. The authors proposed that the phenotype of C282Y heterozygotes and homozygotes may be modified by heterozygosity for mutations which disrupt the function of hepcidin in iron homeostasis, with the severity of iron overload corresponding to the severity of the HAMP mutation.
Among 310 C282Y homozygous HFE patients, Le Gac et al. (2004) found 9 patients with an additional heterozygous HJV mutation, including the L101P (608374.0006) and G320V mutations. Iron indices of 8 of these patients appeared to be more severe than those observed in sex- and age-matched C282Y homozygotes without an HJV mutation. Mean serum ferritin concentrations of the 6 males with an HJV mutation were significantly higher than those of C282Y homozygous males without an HJV mutation.
Using pretherapeutic serum ferritin levels in C282Y homozygotes as a marker of penetrance, Milet et al. (2007) found an association between a common T/C SNP in the 3-prime region of the BMP2 gene (112261), rs235756, and hemochromatosis penetrance. Mean ferritin level, adjusted for age and sex, was 655 ng/ml among TT genotypes, 516 ng/ml in TC genotypes, and 349 ng/ml in CC genotypes. The subjects studied were all homozygous for the common C282Y mutation. The results further suggested an interactive effect on serum ferritin level of rs235756 in BMP2 and a SNP in HJV (608374), with a small additive effect of a SNP in BMP4 (112262).
Le Gac et al. (2008) reported a 47-year-old woman of Sardinian descent who presented with mild hemochromatosis. Genetic analysis showed that she was homozygous for a deletion involving the entire HFE gene; however, her phenotype was relatively mild and similar to that of women homozygous for the common lower-penetrance C282Y mutation. The report indicated that additional genetic and environmental factors must play a role in the pathogenesis of the disease.
Dadone et al. (1982) found saturation of transferrin above 62% to be the best simply measured indicator of genotype: homozygosity was accurately predicted in 92% of cases. The logarithmic scale of serum ferritin concentration was only 71% accurate. The frequency of the hemochromatosis gene was estimated at 0.069 +/- 0.020, corresponding to a heterozygote frequency of 0.13 and a homozygote frequency of 0.005.
Barton et al. (1999) studied the phenotype-genotype correlation in 150 family members (72 males and 78 females) of 61 Caucasian American probands. Thirty-four of the family members had an HFE phenotype. Genotyping was limited to the 2 major alleles, C282Y and H63D. Among the family members, 92% of C282Y homozygotes, 34.5% of C282Y/H63D compound heterozygotes, and none of the H63D homozygotes had the HFE phenotype. In contrast, a few individuals heterozygous for one or the other allele had iron overload. Pseudodominant patterns of inheritance were not infrequently observed. Hence, phenotyping and genotyping are complementary in screening for hemochromatosis among family members of probands.
Mura et al. (2001) studied 545 probands who were homozygous for the C282Y mutation (613609.0001), showed various signs of clinical hemochromatosis, and had been referred for treatment by phlebotomy. Iron loading was found to be significantly lower in females than in males and to be correlated with increasing age in both males and females. A study of 18 same-sex sib pairs showed no correlation of iron marker status between HH sibs and other sibs, indicating a variable phenotypic expression of iron loading independent of the HFE genotype. Mura et al. (2001) also found that transferrin saturation percentage was the best indicator of the hereditary hemochromatosis phenotype in young subjects, and serum ferritin concentration was the best marker of iron overload in these patients.
The superoxide dismutase-2 (SOD2; 147460) val16 allele (147460.0001) has 30 to 40% lower enzyme activity and increases susceptibility to oxidative stress. Valenti et al. (2004) found a significantly increased frequency of the val16 allele among 217 unrelated patients with hereditary hemochromatosis who developed dilated or nondilated cardiomyopathy compared to HH patients without cardiomyopathy and controls (frequencies of 0.67, 0.45, and 0.52, respectively). The val/val genotype conferred a 10.1-fold increased risk for cardiomyopathy in the HH patients. The association was independent of cirrhosis, diabetes, arthropathy, and hypogonadism, and did not apply to ischemic heart disease. Valenti et al. (2004) concluded that the val16 allele increased the risk of cardiomyopathy due to iron overload toxicity and oxidation in HH patients as a result of decreased activity of the SOD2 enzyme.
To test whether common HFE mutations that associate with this condition and predispose to increases in serum iron indices are overrepresented in diabetic populations, Halsall et al. (2003) determined the allele frequencies of the C282Y (613609.0001) and H63D (613609.0002) HFE mutations among a cohort of 552 patients with typical type 2 diabetes mellitus. There was no evidence for overrepresentation of iron-loading HFE alleles in type 2 diabetes mellitus, suggesting that screening for HFE mutations in this population is of no value.
Early diagnosis of hemochromatosis by clinical features is difficult, but important because organ damage can be prevented by early therapy. Hepatic iron is the most sensitive index of preclinical disease; of noninvasive tests, serum ferritin is unreliable, whereas transferrin saturation correlates with hepatic iron content (Rowe et al., 1977; Edwards et al., 1977). Unexplained elevation of transferrin saturation should prompt study for hemochromatosis, and elevated serum iron is a diagnostically valuable finding which can be sought in relatives of full-blown cases.
On the basis of data generated by an ongoing study of hemochromatosis in Brittany, France, Borecki et al. (1990) concluded that percent transferrin saturation is a reliable indicator of the homozygous state but that, contrary to previous studies, there is no evidence for partial expression of this value in heterozygotes.
Phatak et al. (1998) reported that the prevalence of clinically proven and biopsy-proven hemochromatosis combined was 4.5 per 1,000 in a total sample of 16,031 primary care patients and 5.4 per 1,000 in white persons in the sample. The prevalence was higher in men than in women. Diagnosis was achieved by serum transferrin saturation, followed by the same test under fasting conditions and supplemented by serum ferritin levels. Patients with a fasting serum transferrin saturation of 55% or more and a serum ferritin level of 200 micro g/L or more with no other apparent cause were presumed to have hemochromatosis and were offered liver biopsy to confirm the diagnosis.
Feder et al. (1996) viewed hemochromatosis as a model disorder for genetic testing since it is a frequent disorder and effective intervention, namely therapeutic phlebotomy, is available. Cox (1996) discussed the importance of their simple PCR-based test to detect homozygosity for the mutant hemochromatosis gene. Powell et al. (1998) pointed out that a DNA-based test for the HFE gene was commercially available, but its place in the diagnosis of hemochromatosis was still being evaluated.
Screening for Hemochromatosis
From a screening of 1,968 employees of 2 large corporations, Leggett et al. (1990) concluded that the prevalence of significant iron overload due to homozygous hemochromatosis warranting treatment is approximately 1 in 300 among Australians (predominantly Caucasians). They suggested that transferrin saturation should be included in adult health screening programs. Worwood et al. (1991) urged that a regular program be instituted for identifying homozygotes for hemochromatosis on the basis of ferritin concentrations and inviting these individuals to donate frequently to keep the ferritin concentration toward the lower end of the normal range. Such a program would be beneficial both to persons with this common disease and to the blood supply.
In a discussion of the research priorities in hereditary hemochromatosis, Brittenham et al. (1998) commented on anticipating impediments for implementation of a screening program for the disorder: the risk that the genetic information resulting from screening might be used by insurers, employers, or others to deny health care coverage or services to persons identified as being at risk for iron overload; and concern that the diagnosis of hereditary hemochromatosis would lead to changes in self perception, family interactions, and risk-taking behaviors. Because of these considerations, education, counseling, and obtaining informed consent are all important.
Looker and Johnson (1998) did a study to determine the prevalence of an initially elevated serum transferrin saturation and the prevalence of concurrently elevated serum transferrin saturation and serum ferritin levels in the adult population of the United States. They examined 15,839 men and nonpregnant women 20 years of age or older. Depending on the cut-off values used to determine serum transferrin saturation, the prevalence of initially elevated values ranged from 1 to 6%. Approximately 11 to 22% of those with elevated serum transferrin saturation had concurrently elevated serum ferritin levels. Looker and Johnson (1998) concluded that a hemochromatosis screening program that used a cut-off value of greater than 60% to define elevated serum transferrin saturation would identify 1.4 to 2.5 million U.S. adults for further testing.
Hickman et al. (2000) noted that the measurement of transferrin saturation was not suitable for large-scale, automated population screening for HH. The authors developed an automated measurement of unsaturated iron binding capacity and screened 5,182 consecutive blood samples received by a hospital chemical pathology department over 28 consecutive days. Six hundred ninety-seven samples had a value of less than 30 micromoles/liter, the cutoff value for this study. In these samples, measurement of transferrin saturation identified 294 samples for further analysis. HFE C282Y genotyping was possible in 227 of these and identified 9 C282Y homozygotes and 44 C282Y heterozygotes. A clinical diagnosis of HH had been made independently in 2 of the 9 homozygotes. Hickman et al. (2000) concluded that this technique provided a cost-effective screening tool.
Bulaj et al. (2000) examined the usefulness of genetic screening of relatives of probands with hemochromatosis. They studied 291 probands homozygous for mutations in the HFE gene who had presented to a clinic with signs or symptoms of hemochromatosis or who had elevated transferrin-saturation values. They identified 214 homozygous relatives of these 291 homozygous probands. Of the 113 male homozygous relatives (mean age, 41 years), 96 (85%) had iron overload, and 43 (38%) had at least 1 disease-related condition. Of the 52 men over 40 years of age, 27 (52%) had at least 1 disease-related condition. Of the 101 female homozygous relatives (mean age, 44 years), 69 (68%) had iron overload, and 10 (10%) had at least 1 disease-related condition. Of the 43 women over 50 years of age, 7 (16%) had at least 1 disease-related condition. If the proband had a disease-related condition, male relatives were more likely to have morbidity than if the proband had no disease-related condition. Bulaj et al. (2000) concluded that a 'substantial number' of homozygous relatives of patients with hemochromatosis, more commonly men than women, have conditions related to hemochromatosis that had not previously been detected clinically.
Niederau et al. (1985) concluded that HH patients diagnosed in the precirrhotic stage and treated with therapeutic phlebotomy have a normal life expectancy, whereas cirrhotic patients have a shortened life expectancy and a high risk of liver cancer even when complete iron depletion has been achieved. Siemons and Mahler (1987) found that phlebotomy conducted over a 16-month period restored fertility and normal endocrinologic findings in a 37-year-old man with severe hypogonadotropic hypogonadism due to hemochromatosis.
Barton et al. (1998) recommended that therapeutic phlebotomy to remove excess iron be initiated in men with serum ferritin levels of 300 micrograms/L or more and in women with serum ferritin levels of 200 micrograms/L or more, regardless of the presence or absence of symptoms. Typically, therapeutic phlebotomy consists of removal of 450 to 500 mL of blood weekly until the serum ferritin level is 10 to 20 micrograms/L, and maintenance of the serum ferritin level at 50 micrograms/L or less thereafter by periodic removal of blood. Treatment before the development of complications can prevent them; in patients with established iron overload disease, weakness, fatigue, increased hepatic enzyme concentrations, right upper quadrant pain, and hyperpigmentation are often substantially alleviated by therapeutic phlebotomy. Dietary management of hemochromatosis includes avoidance of medicinal iron, mineral supplements, excess vitamin C, and uncooked seafoods. This can reduce the rate of iron reaccumulation, reduce retention of nonferrous metals, and help reduce complications of liver disease, diabetes mellitus, and Vibrio infection.
The frequency of the hemochromatosis gene in Utah was placed at 5.6% (Cartwright et al., 1979). Homozygotes had a frequency of 0.3% and heterozygotes a frequency of 10.6%. A similar gene frequency was estimated for Brittany (Beaumont et al., 1979). Krikker (1982) described the newly established Hemochromatosis Research Foundation, Inc. As justification for its existence, Krikker wrote as follows: 'The incidence of heterozygosity for the hemochromatosis allele in the white population is approximately 10%. The expected incidence of homozygosity is about 2 to 3 per 1000, an estimate supported by the finding of homozygosity in 1 in 333 residents of Utah (Cartwright et al., 1979), 1 in 400 Bretons (Beaumont et al., 1979), and in an autopsy study 1 in 500 Scots (MacSween and Scott, 1973).' In an extensive study of hemochromatosis in Brittany, Lalouel et al. (1985) confirmed the Salt Lake City data (Cartwright et al., 1979; Kravitz et al., 1979).
In the county of Jamtland in central Sweden, an area known in the past for a high prevalence of iron deficiency, Olsson et al. (1983, 1984) screened for iron overload by a laboratory routine that automatically included determination of serum iron and transferrin saturation. They found a prevalence of 0.5% for genetic iron overload, which suggested that 12.8% of the population are gene carriers.
Meyer et al. (1987) used serum ferritin concentration as a screening test for iron overload in 599 Afrikaners living in the South Western Cape, South Africa. Sixteen subjects, all males from different families, had concentrations greater than 400 micrograms/L. Reevaluations 3 and 5 years later included remeasurement of serum ferritin, assessment of alcohol intake, measurements of serum gamma-glutamyltransferase, percentage saturation of transferrin, and HLA typing. The serum ferritin concentration is significantly raised after excessive alcohol consumption; however, the measurement of serum gamma-glutamyltransferase helps resolve the confusion because a serum ferritin concentration above 300 micrograms/L is very unlikely to be the result of alcohol-induced hepatic damage if the gamma-glutamyltransferase is less than 50 units per liter. Of the 16 index persons, 4 were diagnosed as homozygous for the HLA-linked iron-loading gene. Six appeared to be heterozygotes, 3 were heterozygotes who were also abusing alcohol, and 2 did not fit into any of the diagnostic groups. The calculated gene frequency was 0.082, with an expected heterozygote frequency of 0.148. The fact that no females were identified in the study suggested to the authors that their criteria for homozygosity were set too high. When the data were recalculated for the 300 males, the gene frequency became 0.115 and the heterozygote frequency became 0.204. Simon et al. (1987) presented findings they interpreted as fitting well with the hypothesis that 'the hemochromatosis mutation was a rare if not unique event that produced an ancestral HLA marking that was subsequently modified by recombinations and geographical scattering due to migrations.'
Among 11,065 presumably healthy blood donors (5,840 men and 5,225 women), Edwards et al. (1988) found that transferrin saturation of 62% or more after an overnight fast had a frequency of 0.008 in men and 0.003 in women. Detailed studies were performed in 38 persons with values higher than 62%; 35 underwent liver biopsy. Liver iron stores ranged from normal to markedly increased. Twelve sibs with an identical HLA match to a proband underwent liver biopsy, and 11 had increased liver iron stores. Analysis of pedigrees led to the conclusion that 26 of the 38 probands were homozygotes and 12 were heterozygotes. Basing the estimate of the frequency of homozygosity on the data in men, Edwards et al. (1988) arrived at an estimate of 0.0045, corresponding to a gene frequency of 0.067. By means of a screening using transferrin saturation followed by repeat transferrin saturation and serum ferritin, clinical examination, and laparoscopy, Karlsson et al. (1988) concluded that the prevalence of hemochromatosis in Finland is about 5 per 10,000.
Milman et al. (1990) studied 1 Faroese and 4 Danish kindreds with hemochromatosis. Milman (1991) analyzed 179 patients ascertained in Denmark between 1950 and 1985, as well as 13 preclinical subjects ascertained through family studies or high serum transferrin-saturation values. The high frequency of the HFE gene may account, through the mechanism of pseudodominance, for the simulation of dominant inheritance and the consequent debates in the past as to the mode of inheritance of hemochromatosis. Dokal et al. (1991) reported on a family with affected members in 2 generations in a pseudodominant pedigree pattern. The affected father was deceased. The heterozygous mother and all 6 children (3 homozygotes, 3 heterozygotes) were HLA identical (A1B8/A3B14). Affected sibs were recognized in the precirrhotic stage of hemochromatosis by analysis of serum parameters of iron status in combination with magnetic resonance imaging. In the Saguenay-Lac-Saint-Jean region of northeastern Quebec, De Braekeleer (1993) estimated the prevalence of hereditary hemochromatosis to be 0.014, giving a heterozygote frequency of 0.21. These were among the highest frequencies found in white populations. Fertility studies showed that carriers of the gene tended to have more children than noncarriers. However, since the differences were not statistically significant, genetic drift could not be excluded.
In an analysis of 82 unrelated HFE patients and 82 unrelated healthy controls, Jazwinska et al. (1993) found that allele 8 at the D6S105 locus was present in 93% of patients and only 21% of controls, giving an approximate relative risk for this allele of 48.4. HLA-A3 was present in 62% of patients and 26% of controls, giving an approximate relative risk for A3 of 4.8. They concluded that the microsatellite marker D6105 was the closest marker to HFE reported to that date.
Jazwinska et al. (1995) found that hemochromatosis shows a very strong founder effect in Australia, with the majority of patients being of Celtic (Scottish/Irish) origin. By analyzing chromosomes from 26 multiply affected hemochromatosis pedigrees for linkage disequilibrium and genetic heterogeneity, they were able to assign hemochromatosis status unambiguously to 107 chromosomes: 64 as affected and 43 as unaffected. With the serologic marker HLA-A and 4 microsatellite markers, highly significant allelic association with hemochromatosis was found. One predominant ancestral haplotype was present in 33% of 64 affected chromosomes and was associated exclusively with hemochromatosis (haplotype relative risk 903). No other common haplotype was significantly associated with hemochromatosis. Thus, the common mutation probably underlies hemochromatosis in Australian patients, having been introduced into this population on an ancestral haplotype. Furthermore, the candidate HFE region extends between and includes D6S248 and D6S105.
Pozzato et al. (2001) found a high prevalence of HFE gene mutations in the Cimbri population of the Asiago plateau, situated in the Italian region of Veneto. The Cimbri population descends from an ancient tribe of Celtic ancestry who settled on the plateau around the 2nd century B.C. and who preserved their independence and ethnic integrity. In 103 unrelated blood donors with parents and grandparents born in the Asiago plateau, the allele frequencies of the C282Y and H63D mutations were 0.048 and 0.174, respectively. The study confirmed the high prevalence of HFE gene mutations in Celtic populations, and the authors speculated that these mutations gave them selective advantages because of their iron-poor diet. They theorized that a larger amount of iron can be transferred from the mother through the placenta, reducing perinatal mortality and morbidity.
Using a relative risk of 1.0 for the C282Y homozygote, Risch (1997) calculated the risk of the C282Y/H63D compound heterozygote to be 0.00525 and the relative risk of other genotypes to be 0.00015. There appeared to be a modestly increased risk (about 4-fold) associated with homozygosity for H63D. Great haplotype diversity on non-C282Y chromosomes had been observed in patients. This was not surprising, as the disequilibrium on H63D chromosomes spans a much shorter distance (700 kb) than on C828Y chromosomes (more than 7 Mb), consistent with the higher frequency and likely older origin for H63D. Indeed, the disequilibrium analysis of H63D chromosomes provided compelling evidence both for the implication of H63D in hemochromatosis and that HFE is the hemochromatosis gene. Beckman et al. (1997) found that the C282Y mutation is rare or absent in Asiatic (Indian, Chinese) populations. The highest allele frequency they found was in Swedes (7.5%).
Parkkila et al. (1997) suggested a selective advantage of the C282Y mutation on the basis of improved survival during infancy, childhood, and pregnancy in times past, by leading to increased iron absorption and accumulation of larger body iron stores. Although this selection could operate at the level of increased dietary iron absorption, such mutations might also lead to enhanced maternal/fetal iron transport. Such an effect might confer a selective advantage on the fetus under conditions of maternal iron deprivation.
Burt et al. (1998) determined the frequency of the C282Y and H63D HFE mutations in randomly selected adults from Christchurch, New Zealand. Heterozygote frequencies were 13.2% for C282Y and 24.3% for H63D. Heterozygotes for both alleles had significantly higher serum iron concentrations and transferrin saturations; only C282Y heterozygotes had significantly higher serum ferritin concentrations. Five individuals were homozygous for the C282Y mutation; 3 (2 females aged 38, and 1 male aged 71) had persistently elevated serum ferritin levels and liver biopsy findings consistent with hemochromatosis. The remaining 2 C282Y homozygotes (2 females aged 20 and 31) did not have elevated ferritin levels and were not biopsied. The authors commented that the population frequency of C282Y homozygosity was approximately 1 in 200 and that population screening programs should restrict genotyping to individuals with an elevated transferrin saturation.
Steinberg et al. (2001) estimated the prevalence of the C282Y and H63D mutations in the U.S. population as 5.4% and 13.5%, respectively. The prevalence estimates of homozygosity for the C282Y and H63D mutations were 0.26% and 1.89%, respectively, and 1.97% for compound heterozygosity for these 2 alleles. The prevalence estimate for C282Y heterozygosity was 9.54% among non-Hispanic whites, 2.33% among non-Hispanic blacks, and 2.75% among Mexican Americans. The prevalence estimates for HFE mutations were within the expected range for non-Hispanic whites and blacks, but were less than expected for the C282Y mutation among Mexican Americans.
Merryweather-Clarke et al. (1999) retrospectively analyzed 837 random dried blood spot samples from neonatal screening programs in Scandinavia for mutations in the HFE gene. They found that the C282Y allele had a frequency of 2.3% in Greenland, 4.5% in Iceland, 5.1% in the Faroe Islands, and 8.2% in Denmark. The high prevalence of HFE mutations in Denmark suggested that population screening for C282Y could be highly advantageous in terms of preventive health care. Furthermore, long-term follow-up evaluation of C282Y homozygotes and H63D/C282Y compound heterozygotes would provide an indication of the penetrance of the mutations.
Rochette et al. (1999) stated that over 80% of hemochromatosis patients are homozygous for the C282Y mutation in the unprocessed protein. In a proportion of these patients, compound heterozygosity is found for C282Y and H63D. The clinical significance of the second mutation is such that it appears to predispose 1 to 2% of compound heterozygotes to expression of the disease. The distribution of the 2 mutations differs, C282Y being limited to those of northwestern European ancestry, and H63D being found at allele frequencies of more than 5% in Europe, in countries bordering the Mediterranean, in the Middle East, and in the Indian subcontinent. The C282Y mutation occurs on a haplotype that extends 6 Mb or less, suggesting that this mutation arose during the past 2,000 years. The H63D mutation is older and does not occur on such a large extended haplotype, the haplotype in this case extending 700 kb or less. Rochette et al. (1999) found the H63D and C282Y mutations on new haplotypes. In Sri Lanka, they found H63D on 3 new haplotypes and found C282Y on 1 new haplotype, demonstrating that these mutations have arisen independently on this island. The results suggested that the HFE gene has been subject to selection pressure.
In a population of white adults of northern European ancestry in Busselton, Australia, Olynyk et al. (1999) found that 0.5% were homozygous for the C282Y mutation in the HFE gene. However, only half of those who were homozygous had clinical features of hemochromatosis, and one-quarter had serum ferritin levels that remained normal over a 4-year period.
Brown et al. (2001) used National Hospital Discharge Survey and census data to estimate hemochromatosis-associated hospitalization rates for persons 18 years of age and over. From 1979 to 1997, the rate of hemochromatosis-associated hospitalizations was 2.3 per 100,000 persons in the U.S. The rate among persons 60 years of age and over increased more than 60% during this time.
Barton and Acton (2001) screened 1,373 African American controls in 5 regions of the U.S. for the C282Y and H63D mutations in the HFE gene. The frequency of the C282Y/C282Y genotype was 0.00011; that of C282Y/H63D, 0.00067; and that of H63D/H63D, 0.0101. Penetrance-adjusted estimates indicated that approximately 9 per 100,000 African Americans have a hemochromatosis phenotype and 2 common HFE mutations. Hemochromatosis-associated genotype frequencies varied 11.7-fold across regions.
De Juan et al. (2001) analyzed the frequency of the C282Y, H63D, and S65C (613609.0003) HFE gene mutations in 35 unrelated HH patients from the Basque population. Only 20 (57.1%) of the patients were homozygous for the C282Y mutation, while 5 patients were compound heterozygous for C282Y/H63D or H63D/S65C. Eight patients were heterozygous for 1 of the 3 mutations, and 2 patients lacked any of the mutations studied. In a control group of 116 healthy blood donors of Basque origin, de Juan et al. (2001) found allele frequencies of 29.7%, 5.2%, and 3.0% for the H63D, C282Y, and S65C mutations, respectively. The authors suggested that the peculiar genetic characteristics of the Basques could explain the heterogeneity of HH genotypes found in this study, and the presence of other genetic and external factors could explain the severe iron overload and HH in some of the H63D heterozygotes and no mutated genotypes.
The C282Y mutation probably occurred on a single chromosome carrying the ancestral hemochromatosis haplotype, which subsequently was spread by emigration and founder effect. The C282Y mutation is thought to have appeared 60 to 70 generations ago. Milman and Pedersen (2003) hypothesized that the distribution of the C282Y mutation in Europe is consistent with an origin among the Germanic Iron Age population in southern Scandinavia. From this area, the mutation could later be spread by the migratory activities of the Vikings. Milman and Pedersen (2003) found several arguments in favor of the 'Viking hypothesis': first, the highest frequencies (5.1 to 9.7%) of the C282Y mutation are observed in populations in the northern part of Europe, i.e., Denmark, Norway, Sweden, Faroe Islands, Iceland, eastern part of England and the Dublin area, all Viking homelands and settlements. Second, the highest allele frequencies are reported among populations living along the coastlines. Third, the frequencies of the C282Y mutation decline from northern to southern Europe. Intermediate allele frequencies (3.1 to 4.8%) are seen in populations in central Europe. Low allele frequencies (0 to 3.1%) are recognized in populations in southern Europe and the Mediterranean.
Distante et al. (2004) reviewed the evidence on C282Y frequencies, extended haplotypes involving HLA-A and HLA-B alleles, calculations of mutation age, selective advantage, and the relative importance of population migration and cultural change in the neolithic transition in Europe. They concluded that the C282Y mutation occurred in mainland Europe before 4000 B.C.
In a study of 645 Native Americans compared with 43,453 white participants in a hemochromatosis and iron overload screening study, Barton et al. (2006) found that the allele frequencies of HFE C282Y and H63D were significantly lower in Native Americans than in whites.
Matas et al. (2006) studied the prevalence of the C282Y and H63D mutations in 255 non-Ashkenazi Jewish individuals. Analysis of 24 patients who were H63D homozygotes revealed that 12 had secondary causes of iron overload; of those who did not, 2 had symptomatic hemochromatosis, whereas the remaining 10 had only altered iron metabolism, particularly elevated ferritin, without clinical symptoms. Matas et al. (2006) concluded that homozygosity for the H63D mutation confers an increased risk of iron overload and therefore genetic susceptibility to developing hereditary hemochromatosis.
HLA Association
In 50 unselected and unrelated patients with hemochromatosis, Ritter et al. (1984) found a high association with the HLA haplotype A3B14 (relative risk 23.4). One family with this haplotype was traced back to the end of the seventeenth century. Ritter et al. (1984) suggested that the high frequency of the hemochromatosis gene might be the result of a selective advantage of increased iron sequestration under conditions of iron deficiency: homozygous males would not lose reproductive capacity from effects of iron deficiency on testicular function, and females, homozygous and perhaps heterozygous as well, would be better prepared to meet the increased iron demands of pregnancy. Simon et al. (1988) suggested that a single ancient mutation of a gene involved in iron homeostasis resulted in the present-day hemochromatosis allele. This mutation was thought to have occurred on a chromosome 6 carrying HLA-A3 and HLA-B7. Over the years recombination events between the HLA-A and HLA-B loci presumably led to the observed association with other HLA-B alleles on haplotypes carrying HLA-A3, and recombinations between HLA-A and the hemochromatosis locus produced associations with other HLA-A alleles and haplotypes. The original mutation should be progressing toward equilibrium with the HLA alleles, with the residual association resulting either because there has been insufficient time to reach equilibrium or because the association confers a selective advantage (Kushner et al., 1988). A recent recombination event or perhaps a new mutation has placed a hemochromatosis allele on an HLA-A2,B12 chromosome in a population that made a major contribution to the present-day Australian gene pool. Because of the predominant origin of the present-day Australian population, Summers et al. (1989) suggested that this chromosome originated in England or perhaps, in view of the family names of many of the patients, Ireland.
Jouanolle et al. (1990) studied RFLPs from the HLA-A region and identified a significantly high frequency of a particular EcoRI fragment among the hemochromatosis patients who were HLA-A3 in tissue type.
In Denmark, Milman et al. (1988) found the pattern of HLA antigens associated with hemochromatosis to be similar to those reported both in Germany, where HLA-A3,B7 dominated, and in Brittany, Great Britain, and central Sweden, where HLA-A3,B14 dominated. In 74 Danish patients with hemochromatosis and 21 homozygous relatives, Milman et al. (1992) found atypical frequencies of HLA type: A3 was present in 53.6% as compared to 15.1% in the general population. B7 was present in 33.1% as compared with 15.6% in the general population. The 2 most frequent haplotypes were A3,B5 (10.3% vs 0.3%) and A3,B7 (25.6% vs 6.6%).
In South Wales, Cragg et al. (1988) found that 80% of 15 unrelated patients had HLA-A3 compared with 24% of 600 unrelated and unaffected persons. The most common haplotype was HLA-A3,B7. They found no evidence in support of the possibility that either the ferritin heavy chain gene (134770) or HLA class I genes are candidates for the gene mutant in hemochromatosis. In studies of 24 Australian families, Summers et al. (1989) found linkage to HLA in at least 23. The evidence was interpreted as indicating the involvement of a single genetic locus in most (probably all) cases of familial hemochromatosis in Australia. As in all other populations reported, an association of HLA-A3 and HLA-B7 with the disease was found in the Australian cases. In addition, HLA-A2 and HLA-B12 were in significant linkage disequilibrium in patients but not in controls, which might indicate a new mutation or recent recombination between HLA-A and hemochromatosis either in the Australian patient population or in the founding population.
In a review of 57 families with hereditary hemochromatosis, Adams (1992) found 3 pairs of HLA-identical, sex-matched sibs in which the younger sib demonstrated considerably more iron loading than the older sib. In 19 pairs of HLA-identical, sex-matched sibs homozygous for hemochromatosis, the iron loading was more marked in the older sib. There was no evidence of blood loss, difference in alcohol consumption, or dietary iron loading to explain the increased iron loading in the younger sibs.
Yaouanq et al. (1992) used 5 biallelic polymorphisms located in the HLA class I region to test 198 HLA-typed subjects from the families of 22 hemochromatosis patients. The 5 polymorphisms provided sufficient information to identify unequivocally extended restriction haplotypes in all families. The restriction haplotypes cosegregated with the HFE allele and enabled identification of genotypically identical sibs in all families studied. The method avoids the disadvantages of HLA serologic typing and should be useful for genetic counseling in HFE families.
By immunocytochemistry and Western blot analysis, Waheed et al. (1999) showed that the HFE protein colocalizes with and is physically associated with the transferrin receptor (TFRC; 190010) and beta-2-microglobulin (BM2; 109700) in human duodenal crypt enterocytes. Crypt enterocytes exhibited dramatically higher transferrin (TF; 190000)-bound iron uptake than villus cells, but villus cells showed 2 to 3 times higher uptake of ionic iron than crypt cells. Waheed et al. (1999) proposed that the HFE protein modulates the uptake of transferrin-bound iron from plasma by crypt enterocytes and participates in the mechanism by which the crypt enterocytes sense the level of body iron stores. Impairment of this function caused by HFE gene mutations in hereditary hemochromatosis could provide a paradoxical signal in crypt enterocytes that programs the differentiating enterocytes to absorb more dietary iron when they mature into villus enterocytes.
The hypothesis put forward by Waheed et al. (1999) was tested by Fleming et al. (1999), who demonstrated that in homozygous Hfe-deficient mice an increased duodenal expression of the divalent metal transporter (DMT1; 600523) occurred. Using Northern blot analyses, they quantitated duodenal expression of both classes of DMT1 transcripts: 1 containing an iron-responsive element (IRE), called DMT1(IRE), and 1 containing no IRE, called DMT1(non-IRE). Hfe homozygous deficient mice demonstrated an increase in duodenal DMT1(IRE) mRNA (average, 7.7-fold), despite their elevated transferrin saturation and hepatic iron content. Duodenal expression of DMT1(non-IRE) was not increased, nor was hepatic expression of DMT1 increased. These data supported the model for hemochromatosis in which HFE mutations lead to inappropriately low crypt cell iron, with resultant stabilization of DMT1(IRE) mRNA, upregulation of DMT1, and increased absorption of dietary iron.
At the cell surface, HFE complexes with TFRC, increasing the dissociation constant of transferrin (TF) for its receptor 10-fold. HFE does not remain at the cell surface, but traffics with TFRC to transferrin-positive internal compartments. Using a HeLa cell line in which the expression of HFE is controlled by tetracycline, Roy et al. (1999) showed that the expression of HFE reduced uptake of radioactive iron from TF by 33%, but did not affect the endocytic or exocytic rates of TFRC cycling. Therefore, HFE appears to reduce cellular acquisition of iron from TF within endocytic compartments. HFE specifically reduces iron uptake from TF, as non-TF-mediated iron uptake from Fe-nitrilotriacetic acid was not altered. These results explained the decreased ferritin levels seen in the HeLa cell system, and demonstrated the specific control of HFE over the TF-mediated pathway of iron uptake. These results also have implications for the understanding of cellular iron homeostasis in organs such as the liver, pancreas, heart, and spleen that are iron loaded in persons with hereditary hemochromatosis lacking functional HFE.
By Northern blot and competitive RT-PCR analyses, Zoller et al. (1999) detected enhanced expression of the duodenal metal transporter NRAMP2 (SLC11A2; 600523) in the duodenum of HFE patients compared to controls. Sequence analysis failed to detect mutations in NRAMP2 in the 7 patients or 2 controls. The authors proposed that patients with a defective HFE gene and iron-depleted duodenal cells have a compensatory increase in the expression of NRAMP2 and that its blockade may be a key to successful therapy of HFE.
Townsend and Drakesmith (2002) proposed a molecular model for the function of HFE protein and the mechanism by which mutations in HFE lead to hereditary hemochromatosis. They proposed that HFE has 2 mutually exclusive activities in cells: inhibition of uptake or inhibition of release of iron. The balance between serum transferrin saturation and serum transferrin-receptor concentrations determines which of these functions predominates. With this input, HFE enables the intestinal crypt cells and reticuloendothelial system to interpret the body's iron requirements and regulate iron absorption and distribution. Townsend and Drakesmith (2002) suggested that mutations in the HFE gene result in the overabsorption of dietary iron with iron deposition in tissues. The patterns of tissue iron deposition, e.g., in the liver, are consistent with clinical observations of organ dysfunction in hereditary hemochromatosis.
Zoller et al. (2003) studied the mRNA and protein expression and activity of cytochrome b reductase-1 (CYBRD1; 605745) in duodenal biopsies of patients with iron deficiency anemia, hereditary hemochromatosis, and controls. They found that CYBRD1 activity in iron deficiency is stimulated via enhanced protein expression, whereas in hemochromatosis due to mutations in the HFE gene it is upregulated posttranslationally. Hemochromatosis patients with no mutations in HFE did not have increased CYBRD1 activity. Zoller et al. (2003) concluded that there are different kinetics of intestinal iron uptake between iron deficiency and hemochromatosis due to mutations in HFE, and that duodenal iron accumulation in hereditary hemochromatosis due to mutations in HFE and hereditary hemochromatosis due to mutations in other genes is pathophysiologically different.
Drakesmith et al. (2005) found that the Nef protein of human immunodeficiency virus-1 (HIV-1) downregulated macrophage-expressed HFE. Iron and ferritin accumulation were increased in HIV-1-infected ex vivo macrophages expressing wildtype HFE. The effect was lost with Nef-deleted HIV-1 or with infected macrophages from hemochromatosis patients expressing mutant HFE. Iron accumulation in HIV-1-infected wildtype macrophages was paralleled by increased cellular HIV-1 Gag protein expression.
De Sousa et al. (1994) reported a comparative histologic and quantitative analysis of iron distribution in the tissues of mice homozygous and heterozygous for knockout of the beta-2-microglobulin gene, which is complexed with HLA class I molecules. Progressive hepatic iron overload, indistinguishable from that observed in human hemochromatosis, was found only in mice homozygous for the mutated B2M gene.
Rothenberg and Voland (1996) identified a multigene system in the murine major histocompatibility complex that contains excellent candidates for the murine equivalent of the human HFE locus and implicates nonclassic class I genes in the control of iron absorption. This gene system is characterized by multiple copies of 2 head-to-head genes encoded on opposite strands and driven by a common regulatory motif. This regulatory motif has striking homology to the promoter region of the beta-globin gene (141900), a gene obviously involved in iron metabolism, and hence termed beta-globin analogous promoter, beta-GAP or BGAP. Upstream of the BGAP sequence are nonclassic class I genes. At least 1 of these nonclassic class I genes, Q2, is expressed in the gastrointestinal tract, the primary site of iron absorption. Also expressed in the gastrointestinal tract and downstream of the BGAP motif is a second set of putative genes, termed Hephaestus (HEPH). Based on these observations, Rothenberg and Voland (1996) hypothesized that the genes that seemed to be controlled by BGAP regulatory motifs would be responsible for the control of iron absorption. As a test of this hypothesis, they predicted that mice with altered expression of class I gene products, the beta-2-microglobulin knockout mice, would develop iron overload. This prediction was confirmed, and these results indicated to the authors that B2M-associated proteins are involved in the control of intestinal iron absorption and are strong candidates for the site of the mutation in hemochromatosis. The most frequent mutation in the HFE gene responsible for hemochromatosis, C282Y (613609.0001), interferes with the binding of beta-2-microglobulin to the HFE gene product.
Many individuals homozygous for the defective allele of the HFE gene do not develop iron overload, raising the possibility that genetic variation in modifier loci contributes to the hereditary hemochromatosis phenotype. Mice deficient in the product of the B2M class I light chain fail to express HFE and other class I MHC family proteins, and they have been found to manifest many characteristics of the hereditary hemochromatosis phenotype. To determine whether natural genetic variation plays a role in controlling iron overload, Sproule et al. (2001) performed classic genetic analysis of the iron-loading phenotype in B2M-deficient mice in the context of different genetic backgrounds. They found that strain background was a major determinant in iron loading. Sex played a smaller but still significant role. Resistance and susceptibility to iron overload segregated as complex genetic traits in F1 and backcross progeny. These results suggested the existence of naturally variant autosomal and Y chromosome-linked modifier loci that, in the context of mice genetically predisposed by virtue of B2M deficiency, can profoundly influence the severity of iron loading. These results thus provided a genetic explanation for some of the variability of the hereditary hemochromatosis phenotype in humans.
To test the hypothesis that the HFE gene is involved in regulation of iron homeostasis, Zhou et al. (1998) studied the effects of a targeted disruption of the murine homolog of the HFE gene. The HFE-deficient mice showed profound differences in parameters of iron homeostasis. Even on a standard diet, by 10 weeks of age, fasting transferrin saturation was significantly elevated compared with normal littermates, and hepatic iron concentration was 8-fold higher than that of wildtype littermates. Stainable hepatic iron in the HFE mutant mice was predominantly in hepatocytes in a periportal distribution. Iron concentrations in spleen, heart, and kidney were not significantly different from that in littermates. Erythroid parameters were normal, indicating that the anemia did not contribute to the increased iron storage. The study showed that HFE protein is involved in the regulation of iron homeostasis and that mutations in the gene are responsible for hereditary hemochromatosis. Beutler (1998) emphasized the pathologic and clinical importance of the knockout mouse model for hemochromatosis.
The puzzling linkage between genetic hemochromatosis and the histocompatibility loci became even more puzzling when the gene involved, HFE, was identified. Indeed, within the well-defined, mainly peptide-binding, MHC-class I family of molecules, HFE seems to perform an unusual but essential function. Understanding of HFE function in iron homeostasis was only partial; an even more open question was its possible role in the immune system. To advance knowledge in both of these areas, Bahram et al. (1999) studied deletion of the HFE alpha-1 and alpha-2 putative ligand-binding domains in vivo. HFE-deficient mice were analyzed for a comprehensive set of metabolic and immune parameters. Faithfully mimicking human hemochromatosis, mice homozygous for this deletion developed iron overload, characterized by a higher plasma iron content and a raised transferrin saturation as well as an elevated hepatic iron load. The primary defect could, indeed, be traced to an augmented duodenal iron absorption. In parallel, measurement of the gut mucosal iron content as well as iron regulatory proteins allowed a more informed evaluation of various hypotheses regarding the precise role of HFE in iron homeostasis. However, extensive phenotyping of primary and secondary lymphoid organs including the gut provided no compelling evidence for an obvious immune-linked function for HFE.
Clinical studies have demonstrated that the severity of iron loading is highly variable among individuals with identical HFE genotypes. To determine whether genetic factors other than Hfe genotype influence the severity of iron loading in the murine model of hereditary hemochromatosis, Fleming et al. (2001) bred the disrupted murine Hfe allele onto 3 different genetically defined mouse strains (AKR, C57BL/6, and C3H), which differ in basal iron status and sensitivity to dietary iron loading. Although the Hfe -/- mice from all 3 strains demonstrated increased transferrin saturations and liver iron concentrations compared with Hfe +/+ mice, strain differences in severity of iron accumulation were striking. Targeted disruption of the Hfe gene led to hepatic iron levels in Hfe -/- AKR mice that were 2.5 or 3.6 times higher than those of Hfe -/- C3H or Hfe -/- C57BL/6 mice, respectively. The Hfe -/- mice also demonstrated strain-dependent differences in transferrin saturation, with the highest values in AKR mice and the lowest values in C3H mice. These observations demonstrated that heritable factors markedly influence iron homeostasis in response to Hfe disruption. The authors suggested that analysis of mice from crosses between C57BL/6 and AKR mice should allow the mapping and subsequent identification of genes modifying the severity of iron loading in this murine model of hereditary hemochromatosis.
Both in humans and in mouse models, hereditary hemochromatosis is associated with a paucity of iron in reticuloendothelial cells. It has been suggested that HFE modulates uptake of transferrin-bound iron by undifferentiated intestinal crypt cells, thereby programming the absorptive capacity of enterocytes derived from these cells (Trinder et al., 2002). Although the expression of mouse hepcidin (HAMP; 606464), a hepatic regulator of iron transport, is normally greater during iron overload, Hfe -/- mice have inappropriately low expression of Hamp. Nicolas et al. (2003) crossed Hfe -/- mice with transgenic mice overexpressing Hamp and found that Hamp inhibited the iron accumulation normally observed in the Hfe -/- mice. They suggested that the findings argued against the crypt programming model and suggested that failure of Hamp induction contributes to the pathogenesis of hemochromatosis, providing a rationale for the use of HAMP in the treatment of this disease.
Muckenthaler et al. (2003) performed microarray assays to study the changes in duodenal and hepatic gene expression in Hfe-deficient mice. They found alterations in the expression of Hamp as well as unexpected alterations in the expression of Slc39a1 (the mouse ortholog of SLC40A1; 604653) and duodenal cytochrome b (CYBRD1), which encode key iron transport proteins. They proposed that inappropriate regulatory cues from the liver underlie greater duodenal iron absorption, possibly involving the ferric reductase Cybrd1.
Inflammation influences iron balance in the whole organism. A common clinical manifestation of these changes is anemia of chronic disease (ACD; also called anemia of inflammation). Inflammation reduces duodenal iron absorption and increases macrophage iron retention, resulting in low serum iron concentrations (hyposideremia). Despite the protection hyposideremia provides against proliferating microorganisms, this 'iron withholding' reduces the iron available to maturing red blood cells and eventually contributes to the development of anemia. Hepcidin antimicrobial peptide (HAMP; 606464) is a hepatic defensin-like peptide hormone that inhibits duodenal iron absorption and macrophage iron release. HAMP is part of the type II acute phase response and is thought to have a crucial regulatory role in sequestering iron in the context of ACD. Roy et al. (2004) reported that mice with deficiencies in the hemochromatosis gene product, Hfe, mounted a general inflammatory response after injection of lipopolysaccharide but lacked appropriate Hamp expression and did not develop hyposideremia. These data suggested a previously unidentified role for Hfe in innate immunity and ACD.
Ludwiczek et al. (2007) found that the L-type calcium channel blocker nifedipine increased Dmt1 (600523)-mediated cellular iron transport in vitro. In Hfe-null mice and mice with secondary iron overload, nifedipine mobilized iron from the liver and enhanced urinary iron excretion. Mechanistically, the effect resulted from prolonging the iron-transporting activity of Dmt1 and delaying current inactivation.
The first description of hemochromatosis is attributed to Trousseau (1865). His first patient was a 28-year-old man with severe diabetes. Trousseau wrote: 'From the time this man came into the hospital, I was struck by the almost bronzed appearance of his countenance, and the blackish color of his penis.' At autopsy the liver was found to be very large. 'The entire surface of the organ was granular; it was of a uniform grayish-yellow color; it was very dense, resisting pressure so much as to prevent penetration by the finger. It creaked under the scalpel, and the surface of the cut was granular in place of being smooth.'
The hereditary nature of hemochromatosis was emphasized particularly by Sheldon (1935). In his classic monograph entitled 'Haemochromatosis,' Sheldon (1935) reviewed references to a familial or hereditary basis of the disease made by 14 authors and stated: 'Further evidence is greatly desirable on this aspect of the disease, since the fact of an occasional familial incidence must obviously be taken into account in any theory regarding the origin of the disease.'
The pedigree of Nussbaumer et al. (1952) was reproduced by Sorsby (1953).
The ferritin heavy chain gene (FTH; 134770) was mapped to chromosome 11 by somatic cell hybridization (Hentze et al., 1986). Early in situ hybridization studies suggested that another FTH gene lies in the region 6p21.3-p12 (Cragg et al., 1985; McGill et al., 1987). David et al. (1989) noted that 2 H-type ferritin subunits had been identified in porcine spleen, tadpoles, and HeLa cells. suggesting that there may be a second functional FTH locus on chromosome 6. However, in 83 hemochromatosis patients and 84 controls as well as in 19 nuclear families, David et al. (1989) found no significant difference in the FTH gene using 10 restriction enzymes. The authors concluded that the genomic abnormality responsible for HH is not a major deletion of the FTH gene.
Dugast et al. (1990) found that 2 human ferritin heavy chain genes lie near the hemochromatosis locus on 6p. One of these was shown to be a processed pseudogene. Comparison of its sequence with those of other FTH pseudogenes indicated that these pseudogenes may have derived from a functional FTH gene other than that on chromosome 11, raising the possibility that the other gene on 6p may be functional and may be the site of the mutation in hemochromatosis. Zappone et al. (1991) found no major deletions or alterations in the region of 6p containing these 2 ferritin H genes in patients with hemochromatosis. They also described a polymorphism in one of the genes that they had previously shown to be a processed pseudogene. The PIC value of the polymorphism was calculated as 0.49 and it did not correlated with HH. Using a somatic cell hybrid regional mapping panel for the short arm of chromosome 6, as well as linkage analysis in hemochromatosis families and a population study of hemochromatosis patients and normal individuals, Summers et al. (1991) concluded that the FTH pseudogene sequence on chromosome 6, described by Dugast et al. (1990), maps to 6p, centromeric to the glyoxalase (138750) locus and distant from the hemochromatosis locus. Thus, it was excluded as a candidate gene for hemochromatosis.
Robson et al. (1997) reviewed the identification of the probable gene mutant in hemochromatosis. They pointed out that Simon et al. (1976) first reported the association between specific HLA antigens and hemochromatosis and that it took 20 years to identify the strongest candidate gene to that time. They emphasized that formal proof from functional studies was still required to prove that mutations in this gene cause hemochromatosis. They also discussed why the gene has proved so elusive.
Lonjou et al. (1998) contrasted the general concepts of linkage and allelic association. Recombination acts on the genetic map, not on the physical map. On the other hand, the physical map is usually more accurate. Choice of the genetic or physical map for positional cloning by allelic association depends on the goodness of fit of data to each map under an established model. Huntington disease illustrates the usual case in which the greater reliability of physical data outweighs recombinational heterogeneity. Hemochromatosis represents an exceptional case in which unrecognized recombinational heterogeneity retarded positional cloning for a decade. In hemochromatosis, recombinational heterogeneity was demonstrated by the fact that the ratio of physical to genetic distance was 0.97 distally and 6.14 proximally. The power of allelic association was limited by scarcity of markers until microsatellites were introduced and subsequently by failure to recognize that 1 cM corresponds to several Mb in the region telomeric to HLA-A. Finally, HFE was shown to lie more distally than earlier assumed, but the preferred marker D6S105 was still nearly 2 Mb from HFE. Lonjou et al. (1998) suggested that allowance for nonuniform recombination would have saved a decade of fruitless search near HLA-A, 4.6 Mb from HFE. The reasons for preferring 'allelic association' to 'linkage disequilibrium' were spelled out by Edwards (1980).
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