Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and 3 new ferroportin (slc11A3) mutations

Hetet, Gilles; Devaux, Isabelle; Soufir, Nadem; Grandchamp, Bernard; Beaumont, Carole

doi:10.1182/blood-2003-02-0439

Cited by 127 publications

(82 citation statements)

References 29 publications

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“…In this series of patients they found a single novel mutation (p.Thr30Ile) in the coding sequence of L-ferritin in half the familial and in a few of the isolated cases, but not in >500 normal controls. This finding is remarkable because mutations of L-ferritin are extremely rare and associated either with HHCS [15][16][17] or a neurological disorder known as neuroferritinopathy. 19 Although there is no proof that the mutation is the direct cause of the elevated ferritin levels (the mutation could still be only in disequilibrium with the causative one) the threonine residue at position 30, in the N-terminus of the A α-helix of L-ferritin is evolutionary conserved.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 85%

“…A rare dominant trait is hereditary hyperferritinemia/cataract syndrome (HHCS), due to mutation in the IRE element of the 5' untranslated region of L-ferritin mRNA. [15][16][17] The mutation results in lack of repression of L-ferritin translation that becomes independent of iron availability and of iron regulatory protein regulation and occurs also in iron deficiency. Thus in HHCS, the high serum ferritin levels reflect an increased synthesis of the L-ferritin, but not of total body iron, since the L subunit does not participate in iron oxidation and storage.…”

Section: Clara Camaschella and Erika Poggialimentioning

confidence: 99%

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Towards explaining "unexplained hyperferritinemia"

Camaschella¹,

Poggiali²

2009

Haematologica

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© F e r r a t a S t o r t i F o u n d a t i o nIron (NTBI), the toxic moiety of iron, responsible for liver damage and eventually damage to the heart, pancreas and pituitary gland. Very high levels of ferritin may be found in hemochromatosis type 4 or ferroportin disease which does not result from impaired hepcidin but rather from heterozygous mutations of the hepcidin receptor ferroportin. 5 The disease is autosomal dominant and has a variable clinical phenotype. The true ferroportin disease (hemochromatosis type 4a in Table 1) is due to mutant proteins that are not correctly targeted to the cell surface and is characterized by macrophage iron accumulation, low/normal transferrin saturation and iron-restricted erythropoiesis.6 A second form (hemochromatosis type 4b), due to mutant ferroportins that reach the cell surface but are resistant to hepcidin-induced internalization, 7 is characterized by hepatocyte iron accumulation and high transferrin saturation, as in hemochromatosis. The distinction is clinically relevant, because the true ferroportin disease seems not to be associated with clinical complications. These observations strengthen the relevance of assessing serum ferritin always in the context of transferrin saturation ( Figure 1).Ferritin is increased in iron overload secondary to chronic blood transfusions irrespective of the reason and also in the so called iron loading anemias, which include beta-thalassemia syndromes 8 and congenital sideroblastic or dyserythropoietic anemias, 9 characterized by high levels of ineffective erythropoiesis and low hepcidin production. All these conditions are usually well known from the patient's history and may be diagnosed by specific tests. Several methods such as magnetic resonance imaging (MRI) 10 or SQUID 11 have become available to non-invasively assess hepatic iron concentration: however, serial ferritin determinations remain a useful guide to assess iron overload and to monitor iron chelation therapy in these patients. 12Moderate increase of serum ferritin with normal/high transferrin saturation and mild/moderate liver iron accumulation may be common in chronic liver disorders, such as alcoholic liver disease and chronic viral hepatitis. These conditions require attention because iron may amplify the toxic effect of alcohol and viruses, accelerating the evolution towards fibrosis and cirrhosis. In porphyria cutanea tarda hyperferritinemia is a sign of iron overload (in some cases due to HFE mutations) 13 and, like alcohol and chronic hepatitis, is a trigger of porphyria attacks.In the metabolic syndrome (variable combination of hypertension, diabetes, hypertrigliceridemia, obesity, steatohepatitis or fatty liver) moderate elevation of ferritin is common, but usually ferritin levels are disproportionately high in comparison with iron stores, 14 whereas transferrin saturation is not increased.In recent years, new forms of inherited hyperferritinemia not associated with iron overload have been identified, adding new elements for differential diagnosis. A rare d...

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 85%

Section: Clara Camaschella and Erika Poggialimentioning

confidence: 99%

Towards explaining "unexplained hyperferritinemia"

Camaschella¹,

Poggiali²

2009

Haematologica

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“…Interestingly, the addition of hepcidin did not increase iron retention, and the mutant was shown to be resistant to hepcidin-induced degradation. Although the clinical description of the patient was incomplete (16), the mutation appears to confer a phenotype similar to other mutations that mislocalize Fpn.…”

Section: Discussionmentioning

confidence: 99%

The molecular basis of ferroportin-linked hemochromatosis

Domenico

Ward

Nemeth

et al. 2005

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

205

221

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“…9 Genotypic diagnosis of HHCS is straightforward since the observed mutations are closely grouped to a narrow functional region of FTL and may be a useful diagnostic approach, particularly in the rare HHCS kindreds with a mild cataract phenotype. 16,29 The poor correlation within this series between the site of the nucleotide substitution in FTL and severity of the HHCS phenotype arose largely because of the wide variation in phenotype within kindreds. This may indicate true phenotypic variability in individuals with the same HHCS genotype.…”

Section: Discussionmentioning

confidence: 99%

Clinical features and molecular analysis of seven British kindreds with hereditary hyperferritinaemia cataract syndrome

Lachlan¹,

Temple²,

Mumford

2004

Eur J Hum Genet

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Hereditary hyperferritinaemia cataract syndrome (HHCS) is an autosomal dominant disorder characterised by early onset cataracts and increased serum L-ferritin concentration. Affected individuals show nucleotide substitutions in the region of the L-ferritin gene (FTL) that encodes a regulatory sequence within the (mRNA)FTL termed the iron responsive element (IRE). We report the clinical features of seven HHCS kindreds containing 49 individuals with premature cataract. All the probands received diagnoses of HHCS after the incidental discovery of increased serum L-ferritin concentration (median 1420 lg/l; normal range 15 -360 lg/l), in most cases during investigation or screening for anaemia. All the probands developed characteristic 'sunflower' morphology cataracts in childhood (median age at diagnosis 5 years), but had no other phenotypic features. All the affected kindreds showed nucleotide substitutions in FTL that were predicted to disrupt function of the (mRNA)FTL IRE. The severity of the clinical phenotype of HHCS was variable both within and between kindreds and showed no clear relationship to FTL genotype. HHCS should be included in the differential diagnosis of hyperferritinaemia and should be carefully distinguished from hereditary haemochromatosis. Measurement of the serum L-ferritin concentration should be included in the investigation of all individuals with early onset cataracts.

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Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and 3 new ferroportin (slc11A3) mutations

Cited by 127 publications

References 29 publications

Towards explaining "unexplained hyperferritinemia"

Towards explaining "unexplained hyperferritinemia"

The molecular basis of ferroportin-linked hemochromatosis

Clinical features and molecular analysis of seven British kindreds with hereditary hyperferritinaemia cataract syndrome

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