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Query: UNIPROT:P06889 (Mol)
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The effect of five different transferrin variants (TFv1, TFv2, TFv3, TFv4, and TFv5) on the hemoglobin level, mean corpuscular volume (MCV), ferritin level, percent transferrin saturation (%TS), and the unsaturated iron binding capacity (UIBC) was investigated in subjects with defined HFE haplotypes, 919 persons undergoing health screening and 113 patients with clinical hemochromatosis. The most common variant is TFv4; the population distribution of this variant was also studied. None of the variants were found to have an effect on any of the parameters of iron metabolism that were investigated. Moreover, the frequency of these variants in patients with clinically significant hemochromatosis was no different from that in the general population. We conclude that these polymorphisms in transferrin do not play a role in the expression of hemochromatosis, nor do they produce any other significant changes in iron metabolism.
Blood Cells Mol Dis
PMID:The effect of transferrin polymorphisms on iron metabolism. 1066 Apr 86

We report the clinical, biochemical, and genetic characteristics of 13 hemochromatosis patients from Saguenay-Lac-Saint-Jean in whom the first symptoms appeared before age 30. Although the mean age at onset of the first symptoms was 21. 5 years, their mean age at diagnosis was 23.8 years; the diagnosis was particularly delayed among women. Seventy-seven percent of the patients had hypogonadotrophic hypogonadism and 69% heart failure and/or cardiac arrhythmias. Genetic analysis of the HFE gene revealed heterozygosity for the C282Y mutation in 2 patients and for the S65C mutation in 2 others and homozygosity for the H63D mutation in 1 patient. The remaining 8 patients had no identified mutation in the HFE gene, although sequencing of all seven codons and intron-exon junctions was performed (5 patients). All 13 patients fulfill the clinical criteria of juvenile hemochromatosis and represent the largest cluster thus far reported.
Blood Cells Mol Dis 2000 Feb
PMID:Clinical and molecular aspects of juvenile hemochromatosis in Saguenay-Lac-Saint-Jean (Quebec, canada). 1077 71

The identification of the HFE gene involved in hemochromatosis allows genetic tests based on mutation analysis to be performed. However, discrepancies in the correlation between HFE genotypes and iron-loading status have arisen. We investigated 708 patients with various signs or symptoms suggesting a putative iron overload that, nevertheless, did not reach the current criteria for hemochromatosis diagnosis. Most of the patients (91.4%) included in our study displayed one of three classical iron marker values above the threshold defined for iron overloading. HFE mutation analysis allowed us to identify 45.7% of carrier chromosomes in the studied group of patients that showed higher frequencies of HFE mutations compared with controls. In addition, the frequencies of compound C282Y/H63D heterozygous, H63D/H63D homozygous, and C282Y heterozygous genotypes were higher than those in HH probands and controls; they accounted for 16, 5.6, and 22.5% of the patients, respectively. All genotypic groups had a significantly higher value of serum ferritin concentration compared to the normal value; only the C282Y homozygotes and compound heterozygotes with H63D had a transferrin saturation significantly higher than the normal value. On the whole the H63D homozygous and compound heterozygous patients constitute an intermediate phenotypic group between HH and controls. Some of them may reach the critical overloading defined for HH diagnosis along with a potential risk of developing complications, whereas others only show a partial phenotypic expression.
Mol Genet Metab 2000 Apr
PMID:Relation between HFE mutations and mild iron-overload expression. 1087 Aug 47

Amplification of the region of the HFE gene that contains the c.845G-->A (C282Y) mutation is usually performed using one amplimer that binds to a sequence in intron 3 and another that binds to a sequence in intron 4. Previously, a mutation that interferes with efficient binding to the intron 4 site has been described. We now find that another common mutation in intron 3, IVS3 -48c-->g, prevents binding of the amplimer to that site. This polymorphism occurs at a gene frequency of 0.128 in the African-American population and at a frequency of only 0.006 in the European population. DNA samples heterozygous for the IVS3 -48c-->g polymorphism and C282Y were undistinguishable from samples homozygous for the C282Y mutation when they were examined by allele-specific oligonucleotide hybridization (ASOH) and showed only a weak normal band when examined by electrophoresis following restriction endonuclease digestion. Although the polymorphism occurs in a DNA sequence almost identical to the intron 3 splice donor site, we found no evidence of alternative splice forms. Moreover, serum iron, transferrin saturation, and serum ferritin levels were normal in subjects heterozygous for the polymorphism. It appears, therefore, that the main importance of this polymorphism is that it may lead to misdiagnosis of heterozygotes for the C282Y mutation as homozygotes. We therefore recommend exonic amplimers that avoid sites that contain polymorphisms and that can be multiplexed for detection of the c.187C-->G (H63D) and c.845G-->A (C282Y) mutations.
Blood Cells Mol Dis 2000 Jun
PMID:A common intron 3 mutation (IVS3 -48c-->g) leads to misdiagnosis of the c.845G-->A (C282Y) HFE gene mutation. 1095 Sep 43

The MHC class I-related HFE gene appears to be involved in iron metabolism, but its pathogenic mechanism in hemochromatosis remains unknown. Furthermore, very little is known about the regulation of its expression. Hybridization of human tissue Northern blots revealed five different HFE mRNAs, indicating that HFE gene transcription is subject to alternative processes. cDNA selection and RT-PCR performed on HeLa cells clearly demonstrated the occurrence of either differential termination or splicing in HFE transcription. Among the numerous molecules identified, two may have a genuine biological significance.
Blood Cells Mol Dis 2000 Apr
PMID:The HFE gene undergoes alternate splicing processes. 1100 25

Hereditary hemochromatosis (HH) is common among Caucasians; reported disease frequencies vary from 0.3 to 0.8%. Identification of a candidate HFE gene in 1996 was soon followed by the description of two ancestral mutations, i.e., c.845G-->A (C282Y) and c.187C-->G (H63D). To these was recently added the mutation S65C, which may represent a simple polymorphism. The incidence of HH in Greece is unknown but clinical cases are rare. Also unknown is the carrier frequency of the two mutant alleles. A first estimate of the latter is given in the present report. It is based on data from the genetic analysis of 10 unrelated patients of Greek origin who were referred to our center for genotyping and 158 unselected male blood donors. The allele frequencies for the C282Y and H63D mutations were 0.003 and 0.145, respectively. The C282Y allele was detected in 50% of HH patients. This is considerably lower than the frequencies reported for HH patients in the U.S.A. (82%) and France (91 %) and closer to that reported in Italy (64%). Five patients did not carry any known HFE mutation; three may represent cases of juvenile hemochromatosis, given their early onset with iron overload, hypogonadism, and heart disease. We suggest that genetic heterogeneity is more prominent in Southern Europe. It is also possible that the penetrance of the responsible genes is different across the Mediterranean.
Blood Cells Mol Dis 2000 Apr
PMID:Hereditary hemochromatosis: HFE mutation analysis in Greeks reveals genetic heterogeneity. 1100 26

Genetic testing for the C282Y mutation of the HFE gene has been a major advance in the diagnosis of hereditary hemochromatosis. In most studies, more than 90% of typical hemochromatosis patients are homozygous for the C282Y mutation. Large-scale population screening studies in predominantly Caucasian populations have demonstrated a high prevalence of C282Y homozygotes of approximately 1 in 300. Despite this high prevalence by genetic testing, the clinical diagnosis of hemochromatosis and mortality from the disease are much less common. One possibility is the presence of many undiagnosed cases with nonspecific symptoms, and deaths occurring that are attributed to liver disease, diabetes, and heart disease without the recognition of iron overload secondary to hemochromatosis. Another possibility is a high prevalence of nonexpressing homozygotes. In this review, the available data on nonexpressing C282Y homozygotes is collected including information on pathogenesis, environmental interactions, and implications for population screening using genetic testing.
Mol Genet Metab
PMID:Nonexpressing homozygotes for C282Y hemochromatosis: minority or majority of cases? 1100

The application of molecular genetics to haemochromatosis and experimental mutagenesis in animals has transformed our capacity to investigate the unique physiology of iron homeostasis-a key problem in biology and medicine. The identification of HFE, the principal determinant of adult haemochromatosis (HFE1; OMIM 235200) and TfR2, recently implicated in a rarer form of the inherited disorder (HFE3; OMIM 604250), and the promise of candidate genes for juvenile haemochromatosis (HFE2; OMIM 602390) and neonatal haemochromatosis (OMIM 231100) provide the foundation for important studies into the control mechanism of iron balance in humans. The rare conditions atransferrinaemia (OMIM 209300) and acaeruloplasminaemia (OMIM 604290), each associated with tissue iron overload, have already implicated the iron transport ligand transferrin and the copper transporter caeruloplasmin in the control of iron homeostasis. Gene mapping studies in animal mutants with anaemia due to defects in the uptake or tissue transfer of iron have yielded novel proteins involved in iron transport: DMT1 (brush border transporter of ferrous iron) in the mk/mk mouse, hephaestin (basolateral multi-copper ferroxidase) in the sex-linked anaemic mouse (sla) and ferroportin1 (basolateral iron exporter) in zebrafish weh mutants. The discovery of genes that determine heritable defects of iron absorption and regulation in animals and humans thus holds promise for a complete mechanistic understanding of the molecular pathophysiology of iron metabolism.
Hum Mol Genet 2000 Oct
PMID:Haemochromatosis: novel gene discovery and the molecular pathophysiology of iron metabolism. 1100 92

The mechanism that leads to iron overload in hereditary hemochromatosis is not yet fully understood and genes other than HFE may be involved. Nramp2 is an intestinal iron transporter, upregulated by dietary iron deficiency, which also colocalizes with transferrin in recycling endosomes. The purpose of the present study was to analyze the coding region of the Nramp2 gene in 14 hemochromatosis probands which did not carry any HFE mutations on both chromosomes. We confirmed the existence of a polymorphism (1254 T --> C), which presumably is not associated with hereditary hemochromatosis, but we did not find any mutation. On the other hand, we identified 17 splice variants of the Nramp2 mRNA. Eight corresponded to activation of cryptic splicing sequences between exons 3 and 4. They were observed in a majority of hemochromatosis probands and control subjects. This indicates the existence of an important splicing instability in this region. At this stage, the biological significance of these variants is unclear. Our study did not find evidence for the involvement of the Nramp2 gene in hereditary hemochromatosis. The remaining question is whether hemochromatosis probands in our study have iron overload because of environmental factors or due to mutation in gene(s) other than HFE and Nramp2.
Blood Cells Mol Dis 2000 Aug
PMID:Nramp2 analysis in hemochromatosis probands. 1104 33

In the last four years there has been a major change in the approach to diagnosis of the iron overload disorder hereditary haemochromatosis (HH) following the discovery of the gene that is mutated in HH called HFE. In the first part of this review we will give a concise overview of the disease. Also the current literature on the role of HFE in iron absorption and transport at a molecular level and how mutations in HFE may lead to the break down in the regulation of iron homeostasis is reviewed. The second part of the review focuses on the molecular aspects of iron storage. Different chemical forms of storage iron deposits such as ferrihydrite and geotite are present in the iron storage proteins ferritin and haemosiderin. The type of iron storage deposits is thought to be an important factor in determining the degree of iron toxicity and tissue damage in patients with iron overload. Variations in the form of iron deposits in different types of iron overload disease e.g. HH or beta-thalessemia, the site of iron deposition and the clinical treatment used will be discussed.
Int J Mol Med 2000 Dec
PMID:The new iron age. 1107 17


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