Predominance of the HLA-H Cys282Tyr mutation in Austrian patients with genetic haemochromatosis

Datz, Christian; Lalloz, M. R. A.; Vogel, Wolfgang; Graziadei, Ivo; Hackl, Franz; Vautier, Guy; Layton, D. M.; Maier-Dobersberger, Theresia; Ferenci, Péter; Penner, Edward; Sandhofer, F; Bomford, Adrian; Paulweber, Bernhard

doi:10.1016/s0168-8278(97)80312-1

Cited by 77 publications

(39 citation statements)

References 11 publications

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“…In their study, 83% of 178 patients with clinically diagnosed HH were found to be homozygous for the same missense mutation (C282Y) in the HFE gene. The high frequency of the C282Y mutation in patients with HH has been confirmed by other investigators (6)(7)(8)(9)(10)(11)(12)(13). Confirmatory evidence that a defective HFE gene causes HH was provided by recent observations in mice with a targeted disruption of the HFE gene (14).…”

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confidence: 61%

Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum

Waheed

Parkkila

Saarnio

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

210

126

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In hereditary hemochromatosis (HH), intestinal absorption of dietary iron is increased, leading to excessive iron accumulation in tissues and resultant organ damage. The HFE protein, which is defective in HH, normally is expressed in crypt enterocytes of the duodenum where it has a unique, predominantly intracellular localization. In placenta, the HFE protein colocalizes with and forms a stable association with the transferrin receptor (TfR), providing a link between the HFE protein and iron transport. In the present study, we examined the relationship of the HFE protein to the TfR in enterocytes of the human duodenum and measured the uptake of transferrin-bound iron and ionic iron by isolated crypt and villus enterocytes. Immunocytochemistry showed that the HFE protein and TfR both are expressed in the crypt enterocytes. Western blots showed that, as was the case in human placenta, the HFE protein in crypt enterocytes is physically associated with the TfR and with ␤ 2 -microglobulin. The crypt cell fraction exhibited dramatically higher transferrin-bound iron uptake than villus cells. On the other hand, the villus cells showed 2-3 times higher uptake of ionic iron than crypt cells. We propose 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 HH could provide a paradoxical signal in crypt enterocytes that programs the differentiating enterocytes to absorb more dietary iron when they mature into villus enterocytes.

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mentioning

confidence: 61%

Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum

Waheed

Parkkila

Saarnio

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

210

126

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“…Genomic DNA was extracted from peripheral blood leukocytes by standard techniques, and mutation analyses were carried out as described (17). DNA amplification was performed by the polymerase chain reaction with the primers 5'-CTC.AGG.CAC.TCC.TCT.CAA.CC-3' and 5'-TGG.CAA.GGG.TAA.ACA.GAT.…”

Section: Methodsmentioning

confidence: 99%

Lack of evidence for the pathogenic role of iron and HFE gene mutations in Brazilian patients with nonalcoholic steatohepatitis

Deguti

Sipahi

Gayotto

et al. 2003

Braz J Med Biol Res

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The hypothesis of the role of iron overload associated with HFE gene mutations in the pathogenesis of nonalcoholic steatohepatitis (NASH) has been raised in recent years. In the present study, biochemical and histopathological evidence of iron overload and HFE mutations was investigated in NASH patients. Thirty-two NASH patients, 19 females (59%), average 49.2 years, 72% Caucasians, 12% Mulattoes and 12% Asians, were submitted to serum aminotransferase and iron profile determinations. Liver biopsies were analyzed for necroinflammatory activity, architectural damage and iron deposition. In 31 of the patients, C282Y and H63D mutations were tested by PCR-RFLP. Alanine aminotransferase levels were increased in 30 patients, 2.42 ± 1.12 times the upper normal limit on average. Serum iron concentration, transferrin saturation and ferritin averages were 99.4 ± 31.3 g/dl, 33.1 ± 12.7% and 219.8 ± 163.8 µg/dl, respectively, corresponding to normal values in 93.5, 68.7 and 78.1% of the patients. Hepatic siderosis was observed in three patients and was not associated with architectural damage (P = 0.53) or with necroinflammatory activity (P = 0.27). The allelic frequencies (N = 31) found were 1.6 and 14.1% for C282Y and H63D, respectively, which were compatible with those described for the local population. In conclusion, no evidence of an association of hepatic iron overload and HFE mutations with NASH was found. Brazilian NASH patients comprise a heterogeneous group with many associated conditions such as hyperinsulinism, environmental hepatotoxin exposure and drugs, but not hepatic iron overload, and their disease susceptibility could be related to genetic and environmental features other than HFE mutations.

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“…HFE mutations were detected by PCR-RFLP analysis (19). The length of the amplified fragment of exon 4 of the HFE gene is 400 bp.…”

Section: Detection Of C282y and H63d Mutationsmentioning

confidence: 99%

Analysis of HLA-A antigens and C282Y and H63D mutations of the HFE gene in Brazilian patients with hemochromatosis

Bittencourt

Palácios

Couto

et al. 2002

Braz J Med Biol Res

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The hemochromatosis gene, HFE, is located on chromosome 6 in close proximity to the HLA-A locus. Most Caucasian patients with hereditary hemochromatosis (HH) are homozygous for HLA-A3 and for the C282Y mutation of the HFE gene, while a minority are compound heterozygotes for C282Y and H63D. The prevalence of these mutations in non-Caucasian patients with HH is lower than expected. The objective of the present study was to evaluate the frequencies of HLA-A antigens and the C282Y and H63D mutations of the HFE gene in Brazilian patients with HH and to compare clinical and laboratory profiles of C282Y-positive and -negative patients with HH. The frequencies of HLA-A and C282Y and H63D mutations were determined by PCR-based methods in 15 male patients (median age 44 (20-72) years) with HH. Eight patients (53%) were homozygous and one (7%) was heterozygous for the C282Y mutation. None had compound heterozygosity for C282Y and H63D mutations. All but three C282Y homozygotes were positive for HLA-A3 and three other patients without C282Y were shown to be either heterozygous (N = 2) or homozygous (N = 1) for HLA-A3. Patients homozygous for the C282Y mutation had higher ferritin levels and lower age at onset, but the difference was not significant. The presence of C282Y homozygosity in roughly half of the Brazilian patients with HH, together with the findings of HLA-A homozygosity in C282Y-negative subjects, suggest that other mutations in the HFE gene or in other genes involved in iron homeostasis might also be linked to HH in Brazil.

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Predominance of the HLA-H Cys282Tyr mutation in Austrian patients with genetic haemochromatosis

Cited by 77 publications

References 11 publications

Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum

Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum

Lack of evidence for the pathogenic role of iron and HFE gene mutations in Brazilian patients with nonalcoholic steatohepatitis

Analysis of HLA-A antigens and C282Y and H63D mutations of the HFE gene in Brazilian patients with hemochromatosis

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