A novel mutation in the SLC40A1 gene associated with reduced iron export in vitro.

Ferroportin disease is an inherited disorder of iron metabolism and is caused by mutations in the ferroportin gene (SLC40A1). We present a patient with hyperferritinemia, iron overload in the liver with reticuloendothelial distribution and also in the spleen, and under treatment with erythropheresis. A molecular study of the genes involved in iron metabolism (HFE, HJV, HAMP, TFR2, SLC40A1) was undertaken. In vitro functional studies of the novel mutation found in the SLC40A1 gene was performed. The patient was heterozygous for a novel mutation, c.386T>C (p.L129P) in the SLC40A1 gene; some of his relatives were also heterozygous for this mutation. In vitro functional studies of the L129P mutation on ferroportin showed it impairs its capacity to export iron from cells but does not alter its sensitivity to hepcidin. These findings and the iron overload phenotype of the patient suggest that the novel mutation c.386T>C (p.L129P) in the SLC40A1 gene has incomplete penetrance and causes the classical form of ferroportin disease.

Mutations in the HFE, TFR2, and SLC40A1 genes in patients with hemochromatosis.

Hereditary hemochromatosis causes iron overload and is associated with a variety of genetic and phenotypic conditions. Early diagnosis is important so that effective treatment can be administered and the risk of tissue damage avoided. Most patients are homozygous for the c.845G>A (p.C282Y) mutation in the HFE gene; however, rare forms of genetic iron overload must be diagnosed using a specific genetic analysis. We studied the genotype of 5 patients who had hyperferritinemia and an iron overload phenotype, but not classic mutations in the HFE gene. Two patients were undergoing phlebotomy and had no iron overload, 1 with metabolic syndrome and no phlebotomy had mild iron overload, and 2 patients had severe iron overload despite phlebotomy. The patients' first-degree relatives also underwent the analysis. We found 5 not previously published mutations: c.-408_-406delCAA in HFE, c.1118G>A (p.G373D), c.1473G>A (p.E491E) and c.2085G>C (p.S695S) in TFR2; and c.-428_-427GG>TT in SLC40A1. Moreover, we found 3 previously published mutations: c.221C>T (p.R71X) in HFE; c.1127C>A (p.A376D) in TFR2; and c.539T>C (p.I180T) in SLC40A1. Four patients were double heterozygous or compound heterozygous for the mutations mentioned above, and the patient with metabolic syndrome was heterozygous for a mutation in the TFR2 gene. Our findings show that hereditary hemochromatosis is clinically and genetically heterogeneous and that acquired factors may modify or determine the phenotype.

Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination.

Ferroportin exports iron into plasma from absorptive enterocytes, erythrophagocytosing macrophages, and hepatic stores. The hormone hepcidin controls cellular iron export and plasma iron concentrations by binding to ferroportin and causing its internalization and degradation. We explored the mechanism of hepcidin-induced endocytosis of ferroportin, the key molecular event in systemic iron homeostasis. Hepcidin binding caused rapid ubiquitination of ferroportin in cell lines overexpressing ferroportin and in murine bone marrow-derived macrophages. No hepcidin-dependent ubiquitination was observed in C326S ferroportin mutant which does not bind hepcidin. Substitutions of lysines between residues 229 and 269 in the third cytoplasmic loop of ferroportin prevented hepcidin-dependent ubiquitination and endocytosis of ferroportin, and promoted cellular iron export even in the presence of hepcidin. The human ferroportin mutation K240E, previously associated with clinical iron overload, caused hepcidin resistance in vitro by interfering with ferroportin ubiquitination. Our study demonstrates that ubiquitination is the functionally relevant signal for hepcidin-induced ferroportin endocytosis.

Study of total stimulated saliva flow and hyperpigmentation in the oral mucosa of patients diagnosed with hereditary hemochromatosis. Series of 25 cases.

OBJECTIVE: To study lesions in the oral cavity of patients with hereditary hemochromatosis and determine their association with iron overload. STUDY DESIGN: We took a clinical history, examined the pigmentation of the oral mucosa, and measured total stimulated saliva production. We correlated our results with epidemiological, phenotypic, and genotypic findings. Patients with associated diseases or drug therapy causing xerostomia were excluded. RESULTS: We evaluated 25 patients (20 men, mean age 52 years) over a period of 6 months. No patient complained of xerostomia and pigmentation was not detected in the oral mucosa. The total stimulated salivary flow was reduced in 9 patients who had an average ferritin level of 796.5 µg/l. The decline in total stimulated salivary flow was significantly correlated with ferritin levels (p=0.002). Patients with ferritin levels within the normal range also had normal stimulated salivary flow. CONCLUSIONS: We found no pigmented lesions in the oral mucosa; however, we did observe a decrease in total stimulated salivary flow that correlated with ferritin levels. Therefore, hyposialia caused by functional impairment of the salivary glands may be an early marker of iron deposition.

Hiperferritinemia, ferropenia y síndrome metabólico en un paciente con una nueva mutación en el gen TFR2 y otra en el gen FTL. Estudio familiar / Hyperferritinemia, ferropenia and metabolic syndrome in a patient with a new mutation of gene TFR2 and another in gene FTL. A family study

Fundamento y objetivo: La hiperferritinemia es un hallazgo común en la práctica clínica diaria que puede ser congénita o adquirida y no siempre se asocia con sobrecarga férrica. La hiperferritinemia genética puede acompañarse de sobrecarga, como en la hemocromatosis hereditaria, o cursar con cataratas sin sobrecarga, en ese caso es el síndrome hereditario de hiperferritinemia y cataratas. Por otra parte, el síndrome metabólico puede cursar con hiperferritinemia y sobrecarga leve-moderada pero sin aumento de saturación de transferrina. Presentamos una familia con hiperferritinemia.Pacientes y método: Estudio de una familia con hiperferritinemia dual, congénita y adquirida, con análisis de los genes implicados en el metabolismo del hierro. Resultados:Los pacientes con síndrome hereditario de hiperferritinemia y cataratas tienen la mutación c.-167C>T en heterocigosis en el gen FTL. El paciente con síndrome metabólico presenta, además, una nueva mutación en heterocigosis en el gen TFR2 (c.1259G>A, p.Arg420His). Conclusiones: La hiperferritinemia, habitualmente casual, supone para el clínico un reto diagnóstico por sus diversidades fenotípicas y genotípicas, siendo necesario aunar esfuerzos en investigación básica y clínica para la asistencia de los pacientes (AU)

Background and objetives: Hyperferritinemia is a common finding in clinical practice. This condition can be congenital or acquired, although it is not always associated with iron overload. Genetic hyperferritinemia is associated with iron overload, hereditary hemochromatosis, or cataracts that progress without iron overload (hereditary hyperferritinemia-cataract syndrome). Metabolic syndrome is associated with hyperferritinemia and mild iron overload, with no increase in transferrin saturation. We report a family with hyperferritinemia. Patients and methods: We present the study of a family with dual hyperferritinemia (congenital and acquired) and an analysis of the genes involved in iron metabolism. Results: Patients with hereditary hyperferritinemia-cataract syndrome have the mutation c.-167C>T in the FTL gene; patients with metabolic syndrome present a new mutation in the TFR2 gene (c.1259G>A, p.Arg420His).Conclusions: The phenotypic and genotypic diversity of hyperferritinemia makes it a diagnostic challenge for clinicians. Basic research and clinical research should be combined to ensure better patient care (AU)

Hierro y riesgo vascular residual dependiente del perfil lipídico: una relación olvidada / Iron and residual vascular risk lipid profile dependent: a forgotten relationship

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Hierro y riesgo cardiovascular en pacientes con infección por el virus de la inmunodeficiencia humana / Iron and cardiovascular risk in HIV-infected patients

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[Hyperferritinemia, ferropenia and metabolic syndrome in a patient with a new mutation of gene TFR2 and another in gene FTL. A family study]. / Hiperferritinemia, ferropenia y síndrome metabólico en un paciente con una nueva mutación en el gen TFR2 y otra en el gen FTL. Estudio familiar.

BACKGROUND AND OBJECTIVES: Hyperferritinemia is a common finding in clinical practice. This condition can be congenital or acquired, although it is not always associated with iron overload. Genetic hyperferritinemia is associated with iron overload, hereditary hemochromatosis, or cataracts that progress without iron overload (hereditary hyperferritinemia-cataract syndrome). Metabolic syndrome is associated with hyperferritinemia and mild iron overload, with no increase in transferrin saturation. We report a family with hyperferritinemia. PATIENTS AND METHODS: We present the study of a family with dual hyperferritinemia (congenital and acquired) and an analysis of the genes involved in iron metabolism. RESULTS: Patients with hereditary hyperferritinemia-cataract syndrome have the mutation c.-167C>T in the FTL gene; patients with metabolic syndrome present a new mutation in the TFR2 gene (c.1259G>A, p.Arg420His). CONCLUSIONS: The phenotypic and genotypic diversity of hyperferritinemia makes it a diagnostic challenge for clinicians. Basic research and clinical research should be combined to ensure better patient care.

Two novel mutations in the SLC40A1 and HFE genes implicated in iron overload in a Spanish man.

The most common form of hemochromatosis is caused by mutations in the HFE gene. Rare forms of the disease are caused by mutations in other genes. We present a patient with hyperferritinemia and iron overload, and facial flushing. Magnetic resonance imaging was performed to measure hepatic iron overload, and a molecular study of the genes involved in iron metabolism was undertaken. The iron overload was similar to that observed in HFE hemochromatosis, and the patient was double heterozygous for two novel mutations, c.-20G>A and c.718A>G (p.K240E), in the HFE and ferroportin (FPN1 or SLC40A1) genes, respectively. Hyperferritinemia and facial flushing improved after phlebotomy. Two of the patient's children were also studied, and the daughter was heterozygous for the mutation in the SLC40A1 gene, although she did not have hyperferritinemia. The patient presented a mild iron overload phenotype probably because of the two novel mutations in the HFE and SLC40A1 genes.

Papel del hierro en la interacción entre el huésped y el patógeno / The role of iron in the interaction between host and pathogen

El hierro participa en la respuesta a la infección de tal forma que su déficit puede impedir o dificultar el desarrollo de patógenos y su exceso favorecer las infecciones o su gravedad. El hierro es esencial para el crecimiento, supervivencia y virulencia de microorganismos, y como su nivel en los líquidos biológicos es muy bajo, algunos patógenos han desarrollado complejos mecanismos para adquirirlo de forma eficiente. Es esencial comprender el funcionamiento de estos mecanismos para el diseño de nuevos fármacos y vacunas contra estos patógenos (AU)

Iron is essential for both pathogenic microbes and their host. Iron status may influence the occurrence and outcome of infections. For many microorganisms, iron is essential for growth, survival, and synthesis of virulence factors. However, because circulating iron is mostly transported bound to proteins and the level of free serum iron is therefore very low, some pathogens have developed complex systems to acquire iron efficiently. Understanding these systems is essential in the design of pharmaceutical agents and vaccines targeting pathogens with iron-linked virulence (AU)

[The role of iron in the interaction between host and pathogen]. / Papel del hierro en la interacción entre el huésped y el patógeno.

Iron is essential for both pathogenic microbes and their host. Iron status may influence the occurrence and outcome of infections. For many microorganisms, iron is essential for growth, survival, and synthesis of virulence factors. However, because circulating iron is mostly transported bound to proteins and the level of free serum iron is therefore very low, some pathogens have developed complex systems to acquire iron efficiently. Understanding these systems is essential in the design of pharmaceutical agents and vaccines targeting pathogens with iron-linked virulence. In this review, we examine current data on the role of iron in the struggle between host and pathogen to regulate levels of this essential element. We hope that, in the near future, treatments aimed at reducing iron overload will improve the response to current therapies, and help control infection.

[Hereditary hyperferritinemia cataracts syndrome in a Spanish family caused by the A40G mutation (Paris) in the L-ferritin (FTL) gene associated with the mutation H63D in the HFE gene]. / Síndrome hereditario de hiperferritinemia y cataratas en una familia española con la mutación A40G (París) en el gen de la L-ferritina (FTL) asociada a la mutación H63D en el gen HFE.

BACKGROUND AND OBJECTIVE: The cataract-associated increase in serum ferritin without any other data of iron overload is known since 1995 as hyperferritinemia-cataract syndrome (HHCS). More than 100 families have been described all around the world with this syndrome and more than 30 mutations in the L-ferritin (FTL) gene. We introduce a family from Madrid (Spain), with the disease phenotype and a genotype with the A40G mutation, named Paris, and besides carrier of the H63D mutation of the HFE gene. PATIENTS AND METHOD: The proband and his first grade relatives were studied by determining the hemogram, biochemistry, iron metabolism and HFE gene mutations study, as well as by hepatic magnetic resonance imaging and oftalmologic study. Afterwards a molecular study of the coding region for the IRE (iron responsive element) of the FTL gene was done by sequencing. RESULTS: The proband is a male with early cataracts and hyperferritinemia, heterozygous for the H63D and A40G mutations of the HFE and FTL genes, respectively. The mother has the same phenotype (hyperferritinemia and surgery for early cataracts) and genotype (H63D and A40G alleles in heterozygosis). On the other hand, the sister has no cataracts but has hyperferritinemia, is homozygous for H63D and heterozygous for A40G. The father is heterozygous for H63D, but lacks the A40G mutation and the HHCS phenotype. CONCLUSIONS: The HHCS must be included in the differential diagnosis of the hyperferritinemias without iron overload. In turn, hyperferritinemia must be ruled out in an early cataract. The only treatment is ophthalmological, and phlebotomies must be avoided in a false hemochromatosis diagnostic when HFE gene mutations are associated, because of the poor tolerance for causing severe anemia.