Elevated growth differentiation factor 15 expression in patients with congenital dyserythropoietic anemia type I

Tamary, Hannah; Shalev, Hanna; Perez-Avraham, Galit; Zoldan, Meira; Levi, Itai; Swinkels, Dorine W.; Tanno, Toshihiko; Miller, Jeffery L.

doi:10.1182/blood-2008-06-165738

Cited by 122 publications

(102 citation statements)

References 14 publications

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“…Iron loading may be alleviated by ongoing iron loss, such as menstrual bleeding or pregnancies. The study by Tamary on iron overload pathogenesis in CDA I patients supports the notion that high levels of GDF15 contribute to this pathology that, 44 because of its overexpression, occurs together with ineffective erythropoiesis and positively correlates with ferritin levels in adults. In 2011, Casanovas demonstrated that serum hepcidin to ferritin ratio is strongly decreased in CDA patients compared to control subjects; thus showing that serum hepcidin concentrations are inappropriately low.…”

Section: Complications and Therapeutic Approachessupporting

confidence: 54%

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Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach

2012

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Congenital dyserythropoietic anemias belong to a group of inherited conditions characterized by a maturation arrest during erythropoiesis with a reduced reticulocyte production in contrast with erythroid hyperplasia in bone marrow. The latter shows specific morphological abnormalities that allowed for a morphological classification of these conditions mainly represented by congenital dyserythropoietic anemias types I and II. The identification of their causative genes provided evidence that these conditions have different molecular mechanisms that induce abnormal cell maturation and division. Some altered proteins seem to be involved in the chromatin assembly, such as codanin-1 in congenital dyserythropoietic anemia I. The gene involved in congenital dyserythropoietic anemia II, the most frequent form, is SEC23B. This condition seems to belong to a group of diseases attributable to defects in the transport of newly synthesized proteins from endoplasmic reticulum to the Golgi. This review will analyze recent insights in congenital dyserythropoietic anemias types I and II. It will also attempt to clarify the relationship between mutations in causative genes and the clinical phenotype of these conditions. Key words: dyserythropoiesis, congenital dyserythropoietic anemia, red blood cells, inherited anemias.Citation: Iolascon A, Esposito MR, and Russo R. Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach. Haematologica 2012;97(12): 1786-1794. doi:10.3324/haematol.2012 This is an open-access paper. ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nto distinguish without molecular evaluation. 7,8 Recent identification of several causative genes could help reclassify these disorders (Table 1). Variant forms are very rare and this, up to now, has compromised further molecular studies. Linkage studies had previously been the main tool to clarify the genetics of Mendelian disorders; however, extremely rare disorders or sporadic cases caused by de novo variants are not appropriate for this type of study design. Exome sequencing is now becoming technically feasible and more cost-effective due to the recent advances in high-throughput sequence capture methods and next-generation sequencing technologies that have offered new opportunities for research into Mendelian disorders. 9 We suggest that the use of these new technologies will lead to the identification of new causative genes in CDA variants in the near future. In particular, this review will deal with new insights on the two most frequent forms of CDAs: types I and II. Epidemiology of CDAsUntil December 2011, 712 cases from 614 families were included in the German CDA Registry, 10,11 whereas 206Clinical aspects and pathogenesis of CDAs haematologica | 2012; 97 (12) 1787 © F e r r a t a S t o r t i F o u n d a t i o ncases from 183 families were enrolled in the Italian CDA registry (A Iolascon, unpublished data, 2011 Although CDA II patients are to be found right across the Italian peninsula, the maj...

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Section: Complications and Therapeutic Approachessupporting

confidence: 54%

“…Molecular mechanisms of iron overload have been recently characterized. 43,44 In both conditions, iron loading is not dependent on transfusions (but could be increased by them). Iron loading may be alleviated by ongoing iron loss, such as menstrual bleeding or pregnancies.…”

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confidence: 99%

Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach

2012

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“…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.…”

Section: Clara Camaschella and Erika Poggialimentioning

confidence: 99%

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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“…4 Furthermore, GDF15 concentrations are strongly increased in disorders hallmarked by increased ineffective erythropoiesis, such as β-thalassemia, congenital dyserythropoietic anemias or, to a lesser extent, pyruvate kinase deficiency. [4][5][6][7] GDF15 is expressed in several organs, including liver, lung, kidney, and exocrine glands. 8,9 In mice, GDF15 acts as a cardioprotective factor released by the myocardium, and as a neurotrophic factor for midbrain dopaminergic neurons.…”

Section: Introductionmentioning

confidence: 99%

The murine growth differentiation factor 15 is not essential for systemic iron homeostasis in phlebotomized mice

et al. 2012

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Elevated growth differentiation factor 15 expression in patients with congenital dyserythropoietic anemia type I

Cited by 122 publications

References 14 publications

Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach

Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach

Towards explaining "unexplained hyperferritinemia"

The murine growth differentiation factor 15 is not essential for systemic iron homeostasis in phlebotomized mice

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