A Portuguese patient homozygous for the -25G>A mutation of the HAMP promoter shows evidence of steady-state transcription but fails to up-regulate hepcidin levels by iron.

Blood. 2005 Oct 15;106(8):2922-3. A Portuguese patient homozygous for the -25G>A mutation of the HAMP promoter shows evidence of steady-state transcription but fails to up-regulate hepcidin levels by iron. Porto G, Roetto A, Daraio F, Pinto JP, Almeida S, Bacelar C, Nemeth E, Ganz T, Camaschella C. PMID: 16204153 [PubMed - indexed for MEDLINE]Free Article Publication Types, MeSH Terms, SubstancesPublication Types: Letter Research Support, Non-U.S. Gov't MeSH Terms: Antimicrobial Cationic Peptides/genetics* Antimicrobial Cationic Peptides/urine Glycine/genetics* Hemochromatosis/genetics Homozygote* Humans Iron/pharmacology* Mutation/genetics Portugal Promoter Regions, Genetic/genetics* Transcription, Genetic/genetics* Up-Regulation/drug effects* Substances: Antimicrobial Cationic Peptides hepcidin Glycine Iron LinkOut - more resourcesFull Text Sources: HighWire Press EBSCO Other Literature Sources: COS Scholar Universe Medical: Genetics Home Reference - HAMP Gene - Genetics Home Reference Molecular Biology Databases: IRON - HSDB GLYCINE - HSD

Growth hormone (GH)‐induced reconstitution of CD8+ CD28+ T lymphocytes in a rare case of severe lymphopenia associated with Juvenile Haemochromatosis and Turner's syndrome.

Clin Endocrinol (Oxf). 2004 Oct;61(4):437-40. Growth hormone (GH)-induced reconstitution of CD8+ CD28+ T lymphocytes in a rare case of severe lymphopenia associated with Juvenile Haemochromatosis and Turner's syndrome. Porto G, Cruz E, Miranda HP, Porto B, Vasconcelos JC, Lacerda R, Roetto A, Daraio F, Bacelar C. Santo António General Hospital, Porto, Portugal. [email protected] Abstract This paper describes a rare case of Turner's syndrome associated with Juvenile Haemochromatosis and severe lymphopenia, followed-up for a period of 5 years. Because of the indication for treatment with growth hormone (GH), this case was observed as a model to analyse the effects of GH on growth, iron mobilization and lymphocyte reconstitution. For this purpose, a serial study of the T lymphocyte subpopulations CD4+, CD8+, CD8+ CD28+ and CD8+ CD28- was performed by immunophenotyping during the follow-up period. Besides the impact of both phlebotomy treatment and GH on the rapid growth and mobilization of 20.8 g of iron in 136 weeks, the most relevant observation was the finding of a significant expansion of CD8+ T lymphocytes expressing the costimulatory marker CD28 in the setting of the severe lymphopenia. These findings constitute new clinical evidence supporting the notion that the GH/IGF-1 system has an important role on the maintenance of T cell homeostasis in vivo, and that GH may be regarded as a putative therapeutic agent in T lymphocyte reconstitution. PMID: 15473875 [PubMed - indexed for MEDLINE

Comprehensive analysis of mitochondrial and nuclear DNA variations in patients affected by hemoglobinopathies: a pilot study

The hemoglobin disorders are the most common single gene disorders in the world. Previous studies have suggested that they are deeply geographically structured and a variety of genetic determinants influences different clinical phenotypes between patients inheriting identical β-globin gene mutations. In order to get new insights into the heterogeneity of hemoglobin disorders, we investigated the molecular variations on nuclear genes (i.e. HBB, HBG2, BCL11A, HBS1L and MYB) and mitochondrial DNA control region. This pilot study was carried out on 53 patients belonging to different continents and molecularly classified in 4 subgroup: β-thalassemia (β+/β+, β0/β0 and β+/β0)(15), sickle cell disease (HbS/HbS)(20), sickle cell/β-thalassemia (HbS/β+ or HBS/β0)(10), and non-thalassemic compound heterozygous (HbS/HbC, HbO-Arab/HbC)(8). This comprehensive phylogenetic analysis provided a clear separation between African and European patients either in nuclear or mitochondrial variations. Notably, informing on the phylogeographic structure of affected individuals, this accurate genetic stratification, could help to optimize the diagnostic algorithm for patients with uncertain or unknown origin

Altered Erythropoiesis in Mouse Models of Type 3 Hemochromatosis

Type 3 haemochromatosis (HFE3) is a rare genetic iron overload disease which ultimately lead to compromised organs functioning. HFE3 is caused by mutations in transferrin receptor 2 (TFR2) gene that codes for two main isoforms (Tfr2α and Tfr2β). Tfr2α is one of the hepatic regulators of iron inhibitor hepcidin. Tfr2β is an intracellular isoform of the protein involved in the regulation of iron levels in reticuloendothelial cells. It has been recently demonstrated that Tfr2 is also involved in erythropoiesis. This study aims to further investigate Tfr2 erythropoietic role by evaluating the erythropoiesis of two Tfr2 murine models wherein either one or both of Tfr2 isoforms have been selectively silenced (Tfr2 KI and Tfr2 KO). The evaluations were performed in bone marrow and spleen, in 14 days’ and 10 weeks’ old mice, to assess erythropoiesis in young versus adult animals. The lack of Tfr2α leads to macrocytosis with low reticulocyte number and increased hemoglobin values, together with an anticipation of adult BM erythropoiesis and an increased splenic erythropoiesis. On the other hand, lack of Tfr2β (Tfr2 KI mice) causes an increased and immature splenic erythropoiesis. Taken together, these data confirm the role of Tfr2α in modulation of erythropoiesis and of Tfr2β in favoring iron availability for erythropoiesis

A Novel Immunological Assay for Hepcidin Quantification in Human Serum

Contains fulltext : 81054.pdf (publisher's version ) (Open Access)BACKGROUND: Hepcidin is a 25-aminoacid cysteine-rich iron regulating peptide. Increased hepcidin concentrations lead to iron sequestration in macrophages, contributing to the pathogenesis of anaemia of chronic disease whereas decreased hepcidin is observed in iron deficiency and primary iron overload diseases such as hereditary hemochromatosis. Hepcidin quantification in human blood or urine may provide further insights for the pathogenesis of disorders of iron homeostasis and might prove a valuable tool for clinicians for the differential diagnosis of anaemia. This study describes a specific and non-operator demanding immunoassay for hepcidin quantification in human sera. METHODS AND FINDINGS: An ELISA assay was developed for measuring hepcidin serum concentration using a recombinant hepcidin25-His peptide and a polyclonal antibody against this peptide, which was able to identify native hepcidin. The ELISA assay had a detection range of 10-1500 microg/L and a detection limit of 5.4 microg/L. The intra- and interassay coefficients of variance ranged from 8-15% and 5-16%, respectively. Mean linearity and recovery were 101% and 107%, respectively. Mean hepcidin levels were significantly lower in 7 patients with juvenile hemochromatosis (12.8 microg/L) and 10 patients with iron deficiency anemia (15.7 microg/L) and higher in 7 patients with Hodgkin lymphoma (116.7 microg/L) compared to 32 age-matched healthy controls (42.7 microg/L). CONCLUSIONS: We describe a new simple ELISA assay for measuring hepcidin in human serum with sufficient accuracy and reproducibility

Allele frequencies of hemojuvelin gene (HJV) I222N and G320V missense mutations in white and African American subjects from the general Alabama population

BACKGROUND: Homozygosity or compound heterozygosity for coding region mutations of the hemojuvelin gene (HJV) in whites is a cause of early age-of-onset iron overload (juvenile hemochromatosis), and of hemochromatosis phenotypes in some young or middle-aged adults. HJV coding region mutations have also been identified recently in African American primary iron overload and control subjects. Primary iron overload unexplained by typical hemochromatosis-associated HFE genotypes is common in white and black adults in Alabama, and HJV I222N and G320V were detected in a white Alabama juvenile hemochromatosis index patient. Thus, we estimated the frequency of the HJV missense mutations I222N and G320V in adult whites and African Americans from Alabama general population convenience samples. METHODS: We evaluated the genomic DNA of 241 Alabama white and 124 African American adults who reported no history of hemochromatosis or iron overload to detect HJV missense mutations I222N and G320V using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Analysis for HJV I222N was performed in 240 whites and 124 African Americans. Analysis for HJV G320V was performed in 241 whites and 118 African Americans. RESULTS: One of 240 white control subjects was heterozygous for HJV I222N; she was also heterozygous for HFE C282Y, but had normal serum iron measures and bone marrow iron stores. HJV I222N was not detected in 124 African American subjects. HJV G320V was not detected in 241 white or 118 African American subjects. CONCLUSIONS: HJV I222N and G320V are probably uncommon causes or modifiers of primary iron overload in adult whites and African Americans in Alabama. Double heterozygosity for HJV I222N and HFE C282Y may not promote increased iron absorption

Hereditary Hemochromatosis (HFE) genotypes in heart failure: Relation to etiology and prognosis

<p>Abstract</p> <p>Background</p> <p>It is believed that hereditary hemochromatosis (HH) might play a role in cardiac disease (heart failure (HF) and ischemia). Mutations within several genes are HH-associated, the most common being the <it>HFE </it>gene. In a large cohort of HF patients, we sought to determine the etiological role and the prognostic significance of <it>HFE </it>genotypes.</p> <p>Methods</p> <p>We studied 667 HF patients (72.7% men) with depressed systolic function, enrolled in a multicentre trial with a follow-up period of up to 5 years. All were genotyped for the known <it>HFE </it>variants C282Y, H63D and S65C.</p> <p>Results</p> <p>The genotype and allele frequencies in the HF group were similar to the frequencies determined in the general Danish population. In multivariable analysis mortality was not predicted by C282Y-carrier status (HR 1.2, 95% CI: 0.8-1.7); H63D-carrier status (HR 1.0, 95% CI: 0.7-1.3); nor S65C-carrier status (HR 1.2, 95% CI: 0.7-2.0). We identified 27 (4.1%) homozygous or compound heterozygous carriers of <it>HFE </it>variants. None of these carriers had a clinical presentation suggesting hemochromatosis, but hemoglobin and ferritin levels were higher than in the rest of the cohort. Furthermore, a trend towards reduced mortality was seen in this group in univariate analyses (HR 0.4, 95% CI: 0.2-0.9, p = 0.03), but not in multivariate (HR 0.5, 95% CI: 0.2-1.2).</p> <p>Conclusion</p> <p><it>HFE </it>genotypes do not seem to be a significant contributor to the etiology of heart failure in Denmark. <it>HFE </it>variants do not affect mortality in HF.</p