Open AccessFunctional consequences of transferrin receptor‐2 mutations causing hereditary hemochromatosis type 3
Author(s) -
Joshi Ricky,
Shvartsman Maya,
Morán Erica,
Lois Sergi,
Aranda Jessica,
Barqué Anna,
Cruz Xavier,
Bruguera Miquel,
Vagace José Manuel,
Gervasini Guillermo,
Sanz Cristina,
Sánchez Mayka
Publication year - 2015
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.136
Subject(s) - hereditary hemochromatosis , missense mutation , compound heterozygosity , transferrin receptor , biology , mutation , rna splicing , genetics , nonsense mutation , proband , hemochromatosis , receptor , gene , rna
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 ( TFR 2 ) gene. Here, we describe three new HH type 3 Spanish families with four TFR 2 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 TFR 2 mutations (Gln306* and Gln672*) were detected in a pediatric case. We examine the functional consequences of two TFR 2 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 TFR 2 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 TFR 2 mRNA . The reported mutations caused HH type 3 by protein truncation, altering TFR 2 membrane localization or by mRNA splicing defect, producing a nonfunctional TFR 2 protein and a defective signaling transduction for hepcidin regulation. TFR 2 genotyping should be considered in adult but also in pediatric cases with early‐onset of iron overload.