Variable age of onset and clinical severity in transferrin receptor 2 related haemochromatosis: novel observations

Bardou-Jacquet, Édouard; Cunat, Séverine; Beaumont-Epinette, Marie-Pascale; Kannengiesser, Caroline; Causse, Xavier; Sauvion, S.; Pouliquen, B.; Deugnier, Yves; David, Véronique; Loréal, Olivier; Aguilar-Martinez, Patricia; Brissot, Pierre; Jouanolle, Anne–Marie

doi:10.1111/bjh.12350

Cited by 21 publications

(21 citation statements)

References 11 publications

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“…In addition, this missense mutation (p.Gly792Arg) was also recently been reported in trans and in heterozygous state in two patients; one bearing the p.Met705Hisfs*87 mutation and another patient with the variation p.Ala444Thr in TFR2 gene together with the ferroportin mutation p.Gly204Ser (Bardou‐Jacquet et al. ). Here, we reported for the first time a HH type 3 family homozygous for this variation and demonstrated by bioinformatics, computational and coimmunofluorescence studies that indeed this is a pathogenic mutation that affects plasma membrane TFR2 localization in human cell lines (Huh7 and HeLa).…”

Section: Discussionmentioning

confidence: 78%

Functional consequences of transferrin receptor‐2 mutations causing hereditary hemochromatosis type 3

Joshi

Shvartsman

Moran

et al. 2015

Molec Gen & Gen Med

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Hereditary hemochromatosis (HH) type 3 is an autosomal recessive disorder of iron metabolism characterized by excessive iron deposition in the liver and caused by mutations in the transferrin receptor 2 (TFR2) gene. Here, we describe three new HH type 3 Spanish families with four TFR2 mutations (p.Gly792Arg, c.1606-8A>G, Gln306*, and Gln672*). The missense variation p.Gly792Arg was found in homozygosity in two adult patients of the same family, and in compound heterozygosity in an adult proband that also carries a novel intronic change (c.1606-8A>G). Two new nonsense TFR2 mutations (Gln306* and Gln672*) were detected in a pediatric case. We examine the functional consequences of two TFR2 variants (p.Gly792Arg and c.1606-8A>G) using molecular and computational methods. Cellular protein localization studies using immunofluorescence demonstrated that the plasma membrane localization of p.Gly792Arg TFR2 is impaired. Splicing studies in vitro and in vivo reveal that the c.1606-8A>G mutation leads to the creation of a new acceptor splice site and an aberrant TFR2 mRNA. The reported mutations caused HH type 3 by protein truncation, altering TFR2 membrane localization or by mRNA splicing defect, producing a nonfunctional TFR2 protein and a defective signaling transduction for hepcidin regulation. TFR2 genotyping should be considered in adult but also in pediatric cases with early-onset of iron overload.

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Section: Discussionmentioning

confidence: 78%

Functional consequences of transferrin receptor‐2 mutations causing hereditary hemochromatosis type 3

Joshi

Shvartsman

Moran

et al. 2015

Molec Gen & Gen Med

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“…Therefore, it may be expected that the gene encoding transferrin receptor 2 may also be associated with this condition. Disturbances in the TFR2 gene expression may result in cellular damage directly related to oxidative stress [25, 26]. …”

Section: Discussionmentioning

confidence: 99%

Variability of the Transferrin Receptor 2 Gene in AMD

et al. 2014

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Oxidative stress is a major factor in the pathogenesis of age-related macular degeneration (AMD). Iron may catalyze the Fenton reaction resulting in overproduction of reactive oxygen species. Transferrin receptor 2 plays a critical role in iron homeostasis and variability in its gene may influence oxidative stress and AMD occurrence. To verify this hypothesis we assessed the association between polymorphisms of the TFR2 gene and AMD. A total of 493 AMD patients and 171 matched controls were genotyped for the two polymorphisms of the TFR2 gene: c.1892C>T (rs2075674) and c.−258+123T>C (rs4434553). We also assessed the modulation of some AMD risk factors by these polymorphisms. The CC and TT genotypes of the c.1892C>T were associated with AMD occurrence but the latter only in obese patients. The other polymorphism was not associated with AMD occurrence, but the CC genotype was correlated with an increasing AMD frequency in subjects with BMI < 26. The TT genotype and the T allele of this polymorphism decreased AMD occurrence in subjects above 72 years, whereas the TC genotype and the C allele increased occurrence of AMD in this group. The c.1892C>T and c.−258+123T>C polymorphisms of the TRF2 gene may be associated with AMD occurrence, either directly or by modulation of risk factors.

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“…This type is most prevalent in Japan and Italy, but has also been seen in Brazil, France, Thailand and Portugal [1,11,25,30]. Most cases are very rare compound heterozygotes, with over 30 mutations being seen in around 50 families [25,30,41]. A synonymous polymorphism, p.A617A, was found in seven compound heterozygotes in Brazil [29].…”

Section: Non-hfe Hemochromatosismentioning

confidence: 99%

“…Type III hemochromatosis is a mutation of TFR2 [1,2,25,29,30,41]. Whilst the function of TFR2 is not completely understood, it is believed to bind to sense transferrin in hepatocytes by binding to HFE [40].…”

Section: Non-hfe Hemochromatosismentioning

confidence: 99%

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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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Variable age of onset and clinical severity in transferrin receptor 2 related haemochromatosis: novel observations

Cited by 21 publications

References 11 publications

Functional consequences of transferrin receptor‐2 mutations causing hereditary hemochromatosis type 3

Functional consequences of transferrin receptor‐2 mutations causing hereditary hemochromatosis type 3

Variability of the Transferrin Receptor 2 Gene in AMD

Recent advances in hemochromatosis: a 2015 update

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