TFR2-related hereditary hemochromatosis as a frequent cause of primary iron overload in patients from Central-Southern Italy

Radio, Francesca Clementina; Majore, Silvia; Binni, Francesco; Valiante, Michele; Ricerca, Bianca Maria; Bernardo, Carmelilia De; Morrone, Andrea; Grammatico, Paola

doi:10.1016/j.bcmd.2013.08.003

Cited by 20 publications

(24 citation statements)

References 20 publications

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“…In fact, this domain is crucial for the Fe 2 -Tf-TfR2-HFE complex interactions. Nevertheless, another TFR2 missense variant located in the same TfR2 domain (the c.2255GN A, p.Arg752His) is classified as a frequent polymorphism with a genetic modifier capacity [26,28,29]. In our study, the variant c.2255_ allele A was found with a frequency of 0.033 in the group of iron overloaded patients, whereas it was found with a frequency of 0.02 in 50 Portuguese individuals from the general population.…”

Section: Discussionmentioning

confidence: 44%

“…Moreover, both mutations are located within the dimerization domain of the TfR2 protein, near the carboxyl-terminal end, and were predicted by PolyPhen-2 and SIFT as being deleterious. Several other missense variants located at this domain were classified as pathogenic, such as p.Gly792Arg, and p.Thr740Met, because the disruption of that domain is generally associated with protein severe loss of function [26,27]. In fact, this domain is crucial for the Fe 2 -Tf-TfR2-HFE complex interactions.…”

Section: Discussionmentioning

confidence: 99%

“…Our patient presents this novel variant in homozygosity, TFR2: c.[967-1GN C)]; [967-1GN C)], which supports his HH type 3 phenotype. As far as we know, there are only four splicing mutations in TFR2 gene classified as pathogenic and are associated with HH type 3: c.1606-8AN G, c.1538-2AN G, c.2137-1GNA, and c.614+4AN G [26][27][28]30,31].…”

Section: Discussionmentioning

confidence: 99%

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Next-generation sequencing of hereditary hemochromatosis-related genes: Novel likely pathogenic variants found in the Portuguese population

Faria

Silva

et al. 2016

Blood Cells, Molecules, and Diseases

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Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by excessive iron absorption resulting in pathologically increased body iron stores. It is typically associated with common HFE gene mutation (p.Cys282Tyr and p.His63Asp). However, in Southern European populations up to one third of HH patients do not carry the risk genotypes. This study aimed to explore the use of next-generation sequencing (NGS) technology to analyse a panel of iron metabolism-related genes (HFE, TFR2, HJV, HAMP, SLC40A1, and FTL) in 87 non-classic HH Portuguese patients. A total of 1241 genetic alterations were detected corresponding to 53 different variants, 13 of which were not described in the available public databases. Among them, five were predicted to be potentially pathogenic: three novel mutations in TFR2 [two missense (p.Leu750Pro and p.Ala777Val) and one intronic splicing mutation (c.967-1G NC)], one missense mutation in HFE (p.Tyr230Cys), and one mutation in the 5′-UTR of HAMP gene (c. -25GN A). The results reported here illustrate the usefulness of NGS for targeted iron metabolism-related gene panels, as a likely cost-effective approach for molecular genetics diagnosis of non-classic HH patients. Simultaneously, it has contributed to the knowledge of the pathophysiology of those rare iron metabolism-related disorders.

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Section: Discussionmentioning

confidence: 44%

Section: Discussionmentioning

confidence: 99%

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Next-generation sequencing of hereditary hemochromatosis-related genes: Novel likely pathogenic variants found in the Portuguese population

Faria

Silva

et al. 2016

Blood Cells, Molecules, and Diseases

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“…Types I-III are linked to altered or reduced expression of hepcidin [11,25,27], whereas type IV results from reduced iron export [1,28]. Mutations in HFE, HJV, HAMP, TFR2 and SLC40A1 have been linked to the various types of hemochromatosis [11,25,29], each displaying different onsets, severities and prevalences [2,4,9,25,27,[29][30][31][32][33] (Table 1).…”

Section: Genetics and Penetrancementioning

confidence: 97%

Recent advances in hemochromatosis: a 2015 update

2015

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This review focuses on iron metabolism, the genetics of hemochromatosis, current treatment protocols and various screening methods. Even though the most common form of hereditary hemochromatosis, C282Y gene mutations in the HFE gene, has been extensively studied, novel mutations in both HFE and non-HFE genes have been implicated in this disease. These have important implications for the Asia-Pacific region. In overload, deposition of iron in various body tissues leads to toxic damage. Patients commonly present with non-specific symptoms of malaise and lethargy. Biochemical, imaging and genetic testing can be carried out to confirm diagnosis. Venesection forms the mainstay of treatment and at present cascade screening of affected families is recommended over population-level screening.

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“…Since this discovery, a number of cases with HH harboring various TFR2 mutations have been reported, and this condition is classified as HH type 3 [71,72]. The Y245X mutation of this gene in mice, equivalent to Y250X in humans, causes downregulation of hepcidin expression and iron accumulation in the liver [36].…”

Section: Various Types Of Hhmentioning

confidence: 99%

The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis

Kawabata

2017

Int J Hematol

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Hereditary hemochromatosis (HH) is a group of genetic iron overload disorders that manifest with various symptoms, including hepatic dysfunction, diabetes, and cardiomyopathy. Classic HH type 1, which is common in Caucasians, is caused by bi-allelic mutations of HFE. Severe types of HH are caused by either bi-allelic mutations of HFE2 that encodes hemojuvelin (type 2A) or HAMP that encodes hepcidin (type 2B). HH type 3, which is of intermediate severity, is caused by bi-allelic mutations of TFR2 that encodes transferrin receptor 2. Mutations of SLC40A1 that encodes ferroportin, the only cellular iron exporter, causes either HH type 4A (loss-of-function mutations) or HH type 4B (gain-of-function mutations). Studies on these gene products uncovered a part of the mechanisms of the systemic iron regulation; HFE, hemojuvelin, and TFR2 are involved in iron sensing and stimulating hepcidin expression, and hepcidin downregulates the expression of ferroportin of the target cells. Phlebotomy is the standard treatment for HH, and early initiation of the treatment is essential for preventing irreversible organ damage. However, because of the rarity and difficulty in making the genetic diagnosis, a large proportion of patients with non-HFE HH might have been undiagnosed; therefore, awareness of this disorder is important.

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TFR2-related hereditary hemochromatosis as a frequent cause of primary iron overload in patients from Central-Southern Italy

Cited by 20 publications

References 20 publications

Next-generation sequencing of hereditary hemochromatosis-related genes: Novel likely pathogenic variants found in the Portuguese population

Next-generation sequencing of hereditary hemochromatosis-related genes: Novel likely pathogenic variants found in the Portuguese population

Recent advances in hemochromatosis: a 2015 update

The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis

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