New TFR2 mutations in young Italian patients with hemochromatosis

Biasiotto, Giorgio; Camaschella, Clara; Forni, Gian Luca; Polotti, Anna; Zecchina, Gabriella; Arosio, Paolo

doi:10.3324/haematol.11942

Cited by 36 publications

(20 citation statements)

References 8 publications

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“…Together, these results are consistent with a scenario in which TfR2 has a more prominent role than HFE in iron sensing. This is in keeping with the more severe iron overload detected in Tfr2-null mice than in Hfe-deficient ones 29 and with the earlier appearance of iron overload in patients with TFR2-hemochromatosis 18,[30][31][32] than in those with HFE-hemochromatosis.…”

supporting

confidence: 74%

A time course of hepcidin response to iron challenge in patients with HFE and TFR2 hemochromatosis

Girelli¹,

Trombini²,

Busti³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundInadequate hepcidin production leads to iron overload in nearly all types of hemochromatosis. We explored the acute response of hepcidin to iron challenge in 25 patients with HFEhemochromatosis, in two with TFR2-hemochromatosis and in 13 controls. Sixteen patients (10 C282Y/C282Y homozygotes, 6 C282Y/H63D compound heterozygotes) had increased iron stores, while nine (6 C282Y/C282Y homozygotes, 3 C282Y/H63D compound heterozygotes) were studied after phlebotomy-induced normalization of iron stores. Design and MethodsWe analyzed serum iron, transferrin saturation, and serum hepcidin by both enzyme-linked immunosorbent assay and mass-spectrometry at baseline, and 4, 8, 12 and 24 hours after a single 65-mg dose of oral iron. ResultsSerum iron and transferrin saturation significantly increased at 4 hours and returned to baseline values at 8-12 hours in all groups, except in the iron-normalized patients who showed the highest and longest increase of both parameters. The level of hepcidin increased significantly at 4 hours and returned to baseline at 24 hours in controls and in the C282Y/H63D compound heterozygotes at diagnosis. The hepcidin response was smaller in C282Y-homozygotes than in controls, barely detectable in the patients with iron-depleted HFE-hemochromatosis and absent in those with TFR2-hemochromatosis. ConclusionsOur results are consistent with a scenario in which TFR2 plays a prominent and HFE a contributory role in the hepcidin response to a dose of oral iron. In iron-normalized patients with HFE hemochromatosis, both the low baseline hepcidin level and the weak response to iron contribute to hyperabsorption of iron.Key words: hemochromatosis, hepcidin, iron challenge, phlebotomy, transferrin receptor 2.Citation: Girelli D, Trombini P, Busti F, Campostrini N, Sandri M, Pelucchi S, Westerman M, Ganz T, Nemeth E, Piperno A, and Camaschella C. A HFE and TFR2 hemochromatosis. Haematologica 2011;96(4):500-506. doi:10.3324/haematol.2010.033449 time course of hepcidin response to iron challenge in patients with ©2011 Ferrata Storti Foundation. This is an open-access paper.A time course of hepcidin response to iron challenge in patients with HFE and TFR2 hemochromatosis

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supporting

confidence: 74%

A time course of hepcidin response to iron challenge in patients with HFE and TFR2 hemochromatosis

Girelli¹,

Trombini²,

Busti³

et al. 2010

Haematologica

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“…Of the three different disease-causing mutations we selected-OPA1, PYGM, and TFR2-there was no a priori evidence for any effect on splicing from in vitro analysis (Bruno et al 1999;Camaschella et al 2000;Schimpf et al 2008). However, aberrant splicing of OPA1, PYGM, and TFR2 is observed in patients carrying coding and non-coding mutations at other positions in these genes (Schimpf et al 2006;Biasiotto et al 2008;Nogales-Gadea et al 2008). Hexamers corresponding to exonic splicing silencers were obtained from the FAS-hex2 database and scored for loss or gain as described in A.…”

Section: Functional Validation Of a Splicing Silencer Mutationally LImentioning

confidence: 99%

Loss of exon identity is a common mechanism of human inherited disease

Sterne-Weiler¹,

Howard²,

Mort³

et al. 2011

Genome Res.

160

155

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It is widely accepted that at least 10% of all mutations causing human inherited disease disrupt splice-site consensus sequences. In contrast to splice-site mutations, the role of auxiliary cis-acting elements such as exonic splicing enhancers (ESE) and exonic splicing silencers (ESS) in human inherited disease is still poorly understood. Here we use a top-down approach to determine rates of loss or gain of known human exonic splicing regulatory (ESR) sequences associated with either disease-causing mutations or putatively neutral single nucleotide polymorphisms (SNPs). We observe significant enrichment toward loss of ESEs and gain of ESSs among inherited disease-causing variants relative to neutral polymorphisms, indicating that exon skipping may play a prominent role in aberrant gene regulation. Both computational and biochemical approaches underscore the relevance of exonic splicing enhancer loss and silencer gain in inherited disease. Additionally, we provide direct evidence that both SRp20 (SRSF3 ) and possibly PTB (PTBP1) are involved in the function of a splicing silencer that is created de novo by a total of 83 different inherited disease mutations in 67 different disease genes. Taken together, we find that~25% (7154/27,681) of known mis-sense and nonsense disease-causing mutations alter functional splicing signals within exons, suggesting a much more widespread role for aberrant mRNA processing in causing human inherited disease than has hitherto been appreciated.

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“…Synonymous mutations may influence translational stability of the protein due to the codon usage bias (Hunt et al 2009;Shastry 2009). Moreover, several mutations in the TFR2 gene were reported to interfere with normal iron homeostasis leading to iron overload disease -hemochromatosis type III (Pietrangelo 2005;Biasiotto et al 2008). The analysis of risk factors and AMD occurrence, independently of genotypes of the polymorphisms, showed a strong association with age, sex and family history.…”

Section: Discussionmentioning

confidence: 99%

The A Allele of the -576G>A Polymorphism of the Transferrin Gene Is Associated with the Increased Risk of Age-Related Macular Degeneration in Smokers

Wysokiński

Szaflik

Sklodowska

et al. 2011

Tohoku J. Exp. Med.

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Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries, and its pathogenesis is underlined by genetic and environmental factors. Oxidative stress is a major environmental risk factor of AMD; namely, AMD is associated with the increased level of reactive oxygen species, which may be produced in reactions catalyzed by iron present in the retina. Therefore, variability of the genes of iron metabolism may be important in the AMD risk. In the present study, we analyzed the association between AMD and the -576G>A polymorphism of the transferrin gene or the 1892C>T polymorphism of the transferrin receptor 2 (TFR2) gene in 278 patients with AMD and 105 controls. The former polymorphism is located in the promoter region of the transferrin gene and may affect the level of its transcription, while the latter is a synonymous mutation in the exon 16, which may affect the efficiency of translation of TFR2 mRNA. Transferrin and TFR2 are important in iron homeostasis. The A allele of the -576A>G polymorphism was significantly associated with the increased risk of AMD in tobacco smokers, whereas the 1892C>T polymorphism did not influence the risk of AMD related to smoking. Moreover, each polymorphism does not influence the risk of AMD associated with age, sex or the family history of the disease. In conclusion, the A allele of the -576A>G polymorphism of the transferrin gene may increase the risk of AMD in smokers.Keywords: age-related macular degeneration; iron metabolism; transferrin gene; transferrin receptor; genetic polymorphism Tohoku J. Exp. Med., 2011, 223 (4), 253-261. © 2011 Tohoku University Medical Press Age-related macular degeneration (AMD) is the leading cause of vision loss in elderly in developed countries (Gehrs et al. 2006). It is a complex disease affecting the macula, a central part of the retina, leading to the irreversible impairment of central vision (Ding et al. 2009). The frequency of AMD among adults aged more than 75 years exceeds 30% and is expected to increase due to an increasing life expectancy (Liutkeviciene et al. 2010). The early stage of AMD is characterized by druzen formation-a white-yellow deposits in Bruch's membrane under the retinal pigment epithelial (RPE) layer and photoreceptor cells. AMD can develop to one of two advanced forms: dry (atrophic) and wet (exudative, neovascular). Slowly progressing and more common dry AMD is characterized by the presence of an irregular area of depigmentation as a result of the loss of RPE cells and causes a gradual geographic atrophy of the retina. The main feature of wet AMD is choroidal neovascularization with leakage and bleeding, leading to irreversible damage of photoreceptors (Coleman et al. 2008).

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New TFR2 mutations in young Italian patients with hemochromatosis

Cited by 36 publications

References 8 publications

A time course of hepcidin response to iron challenge in patients with HFE and TFR2 hemochromatosis

A time course of hepcidin response to iron challenge in patients with HFE and TFR2 hemochromatosis

Loss of exon identity is a common mechanism of human inherited disease

The A Allele of the -576G>A Polymorphism of the Transferrin Gene Is Associated with the Increased Risk of Age-Related Macular Degeneration in Smokers

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