Transferrin receptor 2 mutations in patients with juvenile hemochromatosis phenotype

Ravasi, Giulia; Rausa, Marco; Pelucchi, Sara; Arosio, Cristina; Greni, Federico; Mariani, Raffaella; Pelloni, Irene; Silvestri, Laura; Pineda, Pedro; Camaschella, Clara; Piperno, Alberto

doi:10.1002/ajh.24202

Cited by 9 publications

(6 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cardiomyopathy most frequently occurs in the severe forms of iron overload (68,86). However, patients with adult hemochromatosis have an increased risk of cardiomyopathy compared to healthy controls (87).…”

Section: Cardiac Damagementioning

confidence: 99%

“…It is caused by mutations of TFR2, whose allele prevalence was estimated between 0.0001 and 0.0004 (128). shown that severe mutations could lead to juvenile-like hemochromatosis and increased iron indices in childhood (86,134,135). Mutations are most often private [reported in HGMD ( 130)] although the 1780-1791del (AVAQ 594-597) was found in a few patients worldwide (136,137), and a cluster of the p.Tyr250* mutation was found in Sicily (134,138).…”

Section: Hemochromatosis Type-3 (Omim #604250)mentioning

confidence: 99%

See 1 more Smart Citation

Inherited iron overload disorders

Piperno

Pelucchi

Mariani

2020

Transl Gastroenterol Hepatol

Self Cite

View full text Add to dashboard Cite

Hereditary iron overload includes several disorders characterized by iron accumulation in tissues, organs, or even single cells or subcellular compartments. They are determined by mutations in genes directly involved in hepcidin regulation, cellular iron uptake, management and export, iron transport and storage. Systemic forms are characterized by increased serum ferritin with or without high transferrin saturation, and with or without functional iron deficient anemia. Hemochromatosis includes five different genetic forms all characterized by high transferrin saturation and serum ferritin, but with different penetrance and expression. Mutations in HFE, HFE2, HAMP and TFR2 lead to inadequate or severely reduced hepcidin synthesis that, in turn, induces increased intestinal iron absorption and macrophage iron release leading to tissue iron overload. The severity of hepcidin down-regulation defines the severity of iron overload and clinical complications. Hemochromatosis type 4 is caused by dominant gain-of-function mutations of ferroportin preventing hepcidin-ferroportin binding and leading to hepcidin resistance. Ferroportin disease is due to loss-of-function mutation of SLC40A1 that impairs the iron export efficiency of ferroportin, causes iron retention in reticuloendothelial cell and hyperferritinemia with normal transferrin saturation.Aceruloplasminemia is caused by defective iron release from storage and lead to mild microcytic anemia, low serum iron, and iron retention in several organs including the brain, causing severe neurological manifestations. Atransferrinemia and DMT1 deficiency are characterized by iron deficient erythropoiesis, severe microcytic anemia with high transferrin saturation and parenchymal iron overload due to secondary hepcidin suppression. Diagnosis of the different forms of hereditary iron overload disorders involves a sequential strategy that combines clinical, imaging, biochemical, and genetic data. Management of iron overload relies on two main therapies: blood removal and iron chelators. Specific therapeutic options are indicated in patients with atransferrinemia, DMT1 deficiency and aceruloplasminemia.

show abstract

Section: Cardiac Damagementioning

confidence: 99%

Section: Hemochromatosis Type-3 (Omim #604250)mentioning

confidence: 99%

Inherited iron overload disorders

Piperno

Pelucchi

Mariani

2020

Transl Gastroenterol Hepatol

Self Cite

View full text Add to dashboard Cite

show abstract

“…For the second family the genotype-phenotype correlation was more complex, the c.998C>T p.(Pro333Leu) variant of TFR2 is at for binding to saturated transferrin. 5,6 This interaction was further demonstrated by functional studies by Ravasi et al 7 The variant was previously described only in homozygosis, in two subjects from two different case series affected by type 3 HH with autosomal recessive inheritance. 5,7 The genotype identified in the proband, does not permit to…”

mentioning

confidence: 70%

Testing for rare types of Hereditary Hemochromatosis. A genetic study of two Italian families affected by early onset iron overload

Atanasio

Bernabini

Consagra

et al. 2023

Int J Lab Hematology

View full text Add to dashboard Cite

“…Current recommendations suggest a stepwise approach (single-gene testing) in which sequencing should be made initially according to clinical features (i.e., prioritizing HJV and HAMP in patients with early-onset and severe iron overload) [8]. While this is reasonable, it is time consuming and does not take appropriately into account the emerging phenotype overlaps between different forms of HH [20][21][22][23], the possible occurrence of digenic inheritance or the presence of rare and severe HFE mutations, and the variable phenotype of ferroportin mutation [1]. Previous studies demonstrated the feasibility, sensitivity and cost-effectiveness of NGS-targeted gene panels and exome sequencing in patients suspected for non-HFE hemochromatosis and Ferroportin disease [24][25][26][27].…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Mutations by Targeted NGS Panel in Patients with Hyperferritinemia

Ravasi

Pelucchi

Bertola

et al. 2021

Genes

Self Cite

View full text Add to dashboard Cite

Background. Several inherited diseases cause hyperferritinemia with or without iron overload. Differential diagnosis is complex and requires an extensive work-up. Currently, a clinical-guided approach to genetic tests is performed based on gene-by-gene sequencing. Although reasonable, this approach is expensive and time-consuming and Next Generation Sequencing (NGS) technology may provide cheaper and quicker large-scale DNA sequencing. Methods. We analysed 36 patients with non-HFE-related hyperferritinemia. Liver iron concentration was measured in 33 by magnetic resonance. A panel of 25 iron related genes was designed using SureDesign software. Custom libraries were generated and then sequenced using Ion Torrent PGM. Results. We identified six novel mutations in SLC40A1, three novel and one known mutation in TFR2, one known mutation and a de-novo deletion in HJV, and a novel mutation in HAMP in ten patients. In silico analyses supported the pathogenic role of the mutations. Conclusions. Our results support the use of an NGS-based panel in selected patients with hyperferritinemia in a tertiary center for iron metabolism disorders. However, 26 out of 36 patients did not show genetic variants that can individually explain hyperferritinemia and/or iron overload suggesting the existence of other genetic defects or gene-gene and gene-environment interactions needing further studies.

show abstract

Transferrin receptor 2 mutations in patients with juvenile hemochromatosis phenotype

Cited by 9 publications

References 8 publications

Inherited iron overload disorders

Inherited iron overload disorders

Testing for rare types of Hereditary Hemochromatosis. A genetic study of two Italian families affected by early onset iron overload

Identification of Novel Mutations by Targeted NGS Panel in Patients with Hyperferritinemia

Contact Info

Product

Resources

About