Premium
Ferroportin Diseases: Functional Studies, a Link Between Genetic and Clinical Phenotype
Author(s) -
Détivaud Lénaïck,
Island MarieLaure,
Jouanolle AnneMarie,
Ropert Martine,
BardouJacquet Edouard,
Le Lan Caroline,
Mosser Annick,
Leroyer Patricia,
Deugnier Yves,
David Véronique,
Brissot Pierre,
Loréal Olivier
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22396
Subject(s) - ferroportin , biology , hepcidin , phenotype , mutant , mutation , loss function , genetics , transferrin saturation , gene , transferrin , transferrin receptor , ferritin , cell , endocrinology , immunology , biochemistry , iron homeostasis , serum ferritin , inflammation
Ferroportin ( FPN ) mediates iron export from cells and this function is modulated by serum hepcidin. Mutations in the FPN gene ( SLC 40 A 1 ) lead to autosomal dominant iron overload diseases related either to loss or to gain of function, and usually characterized by normal or low transferrin saturation versus elevated transferrin saturation, respectively. However, for the same mutation, the phenotypic expression may vary from one patient to another. Using in vitro overexpression of wild‐type or mutant FPN proteins, we characterized the functional impact of five recently identified FPN gene mutations regarding FPN localization, cell iron status, and hepcidin sensitivity. Our aim was to integrate functional results and biological findings in probands and relatives. We show that while the p. A rg371 G ln ( R 371 Q ) mutation had no impact on studied parameters, the p. T rp158 L eu ( W 158 L ), p. A rg88 G ly ( R 88 G ), and p. A sn185 A sp ( N 185 D ) mutations caused an iron export defect and were classified as loss‐of‐function mutations. The p. G ly204 S er ( G 204 S ) mutation induced a gain of FPN function. Functional studies are useful to determine whether or not a FPN gene mutation found in an iron overloaded patient is deleterious and to characterize its biological impact, especially when family studies are not fully informative and/or additional confounding factors may affect bio‐clinical expression.