Functional consequences of transferrin receptor-2 mutations causing hereditary hemochromatosis type 3
Author
Joshi, Ricky
Shvartsman, Maya
Morán, Erica
Lois, Sergi
Aranda, Jessica
Barqué, Anna
De la Cruz, Xavier
Bruguera, Miquel
Vagace, José Manuel
Gervasini, Guillermo
Sanz, Cristina
Sánchez, Mayka
Publication date
2015ISSN
2324-9269
Abstract
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.
Document Type
Article
Document version
Published version
Language
English
Subject (CDU)
57 - Biological sciences in general
Keywords
Mutacions
Transferrina-2
Hemocromatosi hereditària tipus 3
Mutaciones
Transferrina-2
Hemocromatosis hereditaria tipo 3
Mutations
Transferrin-2
Hereditary hemochromatosis type 3
Pages
12
Publisher
John Wiley & Sons
Collection
3; 3
Is part of
Molecular Genetics & Genomic Medicine
Citation
Joshi, Ricky; Shvartsman, Maya; Morán, Erica [et al.]. Functional consequences of transferrin receptor-2 mutations causing hereditary hemochromatosis type 3. Molecular Genetics & Genomic Medicine, 2015, 3(3), p. 221-232. Disponible en: <https://onlinelibrary.wiley.com/doi/10.1002/mgg3.136>. Fecha de acceso: 20 ene. 2022. DOI: 10.1002/mgg3.136
This item appears in the following Collection(s)
- Ciències de la Salut [740]
Rights
2015 - The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0/