Clinical and pathologic findings in hemochromatosis type 3 due to a novel mutation in transferrin receptor 2 gene

Girelli, Domenico; Bozzini, Claudia; Roetto, Antonella; Alberti, Federica; Daraio, Filomena; Colombari, Romano; Olivieri, Oliviero; Corrocher, Roberto; Camaschella, Clara

doi:10.1053/gast.2002.32984

Cited by 131 publications

(65 citation statements)

References 34 publications

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“…A homologue of TfR1, termed transferrin receptor 2 (TfR2), was identified in 1999 (22). While the exact role of TfR2 in iron metabolism is unknown, it is evident that it plays an important function in maintaining iron homeostasis, because mutations in TfR2 lead to a form of hereditary hemochromatosis (type 3) (3,11,14,24,29). TfR2 is highly expressed in the liver (22).…”

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Defective trafficking and localization of mutated transferrin receptor 2: implications for type 3 hereditary hemochromatosis

Wallace¹,

Summerville²,

Crampton³

et al. 2008

American Journal of Physiology-Cell Physiology

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Defective trafficking and localization of mutated transferrin receptor 2: implications for type 3 hereditary hemochromatosis

Wallace¹,

Summerville²,

Crampton³

et al. 2008

American Journal of Physiology-Cell Physiology

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“…So far only a limited number of subjects has been analysed for TfR2, with the identification of 17 different significant mutations. [2][3][4][5][6][7][8][9][10] In this study, we developed DHPLC conditions to detect all DNA variations in the 18 exons and flanking regions. They consisted in analysing 14 amplicons on a Transgenomic WAVE TM system at a minimum of 2 different temperatures.…”

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confidence: 99%

New TFR2 mutations in young Italian patients with hemochromatosis

et al. 2008

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New TFR2 mutations in young Italian patients with hemochromatosisThis work describes the identification of two subjects with young-age iron overload carrying new causative mutations in transferrin receptor-2 gene. One was compound heterozygous (Asn411del/Ala444Thr) and the second was homozygous for a mutation affecting RNA splicing (IVS17+5636G>A). Another mutation (His33Asn) and a polymorphism were found in a group of 50 controls. Haematologica 2008 Feb; 93:(2) 309-310. DOI: 10.3324/haematol.11942 Genetic analysis of hereditary hemochromatosis (HH) identified various genes whose mutations lead to iron overload.1 HFE is responsible for the most common, adult onset form of HH, while HAMP and HJV genes are responsible for the juvenile types of HH, with fast and severe progression of iron overload.1 Also transferrin receptor-2 (TfR2) is associated with HH in a few cases, often diagnosed at young age.2 Furthermore, ferroportin is responsible for a different, dominant form of iron overload with variable iron deposition in hepatocytes or in reticuloendothelial cells.1 Despite the improvements in genetic analyses of HH, identifying defects in large and complex genes like TfR2, which has 18 exons, remains difficult. So far only a limited number of subjects has been analysed for TfR2, with the identification of 17 different significant mutations.2-10 In this study, we developed DHPLC conditions to detect all DNA variations in the 18 exons and flanking regions. They consisted in analysing 14 amplicons on a Transgenomic WAVE TM system at a minimum of 2 different temperatures. We initially studied the DNA from 50 Italian control subjects with normal transferrin saturation (TS) and serum ferritin (SF) values. We found an intronic polymorphism (IVS3+49C>A) and a c.DNA 97C>A transversion (Genebak access: NM_003227.3), causing the amino acid substitution His33→Asn. This modifies His33 in the cytosolic domain, which is conserved in mouse and dog TfR2, aspargine in rat, and it is not expected to have major structural consequences. The finding of two DNA variations in a small control group suggests that heterozygous TfR2 mutations may be rather common. In fact, 7 of the 21 mutations so far reported are at the heterozygous state ( Figure 1) and their effects on TfR2 functionality are unknown. In a retrospective analysis of a small series of 33 patients with abnormally high SF and TS, and exclusion of HFE hemochromatosis or causes of secondary iron overload, 1 we identified two Italian cases with causative mutations (Table 1). Patient #1 was a 21-year-old woman who presented with symptoms of fatigue. She showed high values of TS (>100%) and of SF (~1,000 µg/L) and liver iron concentration (LIC) was relatively high for her age, but no signs of organ involvement. She was compound heterozygous for the c.1330G>A mutation in exon 10 and for the deletion of the triplet AAC (c.1231-3 del) in exon 9, which causes the substitution of Ala444→Thr and the deletion of Asn411 respectively. Asn411 is the first of a tandem of two asparagines and...

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“…Paradójicamente los niveles del mRNA de Tf disminuyen y el mRNA del TfR no se altera 67 . A pesar de que mutaciones en el TfR se asocian con la aparición de hemocromatosis [68][69][70][71][72] , y saturaciones elevadas de Tf, con un mayor riesgo de mortalidad respecto a todas las causas [73][74][75] , estos elementos no se han descrito en la EA.…”

Section: Dmt1unclassified

Proponiendo biomarcadores para evaluar las alteraciones en la homeostasis cerebral de hierro y su relación con la fisiopatología de la Enfermedad de Alzheimer

Tapia-Saavedra

2007

Rev. chil. neuro-psiquiatr.

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Clinical and pathologic findings in hemochromatosis type 3 due to a novel mutation in transferrin receptor 2 gene

Cited by 131 publications

References 34 publications

Defective trafficking and localization of mutated transferrin receptor 2: implications for type 3 hereditary hemochromatosis

Defective trafficking and localization of mutated transferrin receptor 2: implications for type 3 hereditary hemochromatosis

New TFR2 mutations in young Italian patients with hemochromatosis

Proponiendo biomarcadores para evaluar las alteraciones en la homeostasis cerebral de hierro y su relación con la fisiopatología de la Enfermedad de Alzheimer

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