Ferroportin diseases: functional studies, a link between genetic and clinical phenotype.
Ferroportin (FPN) mediates iron export from cells and this function is modulated by serum hepcidin. Mutations in the FPN gene (SLC40A1) 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.Arg371Gln (R371Q) mutation had no impact on studied parameters, the p.Trp158Leu (W158L), p.Arg88Gly (R88G), and p.Asn185Asp (N185D) mutations caused an iron export defect and were classified as loss-of-function mutations. The p.Gly204Ser (G204S) 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.
CHU Rennes, French Reference Centre for Rare Iron Overload Diseases of Genetic Origin, Rennes, France; CHU Rennes, Department of Molecular Biology, Rennes, France; CHU Rennes, Department of Liver Diseases, Rennes, France; INSERM UMR 991, Equipe Fer et Foie, Rennes, France.
Lénaïck
L
Détivaud
Marie-Laure
ML
Island
Anne-Marie
AM
Jouanolle
Martine
M
Ropert
Edouard
E
Bardou-Jacquet
Caroline
C
Le Lan
Annick
A
Mosser
Patricia
P
Leroyer
Yves
Y
Deugnier
Véronique
V
David
Pierre
P
Brissot
Olivier
O
Loréal
D027682:Cation Transport Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005293:Ferritins / Q000378:metabolism; D015870:Gene Expression; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D014168:Transferrin / Q000378:metabolism; D000098742:Ferroportin
D027682:Cation Transport Proteins; D014168:Transferrin; D000098742:Ferroportin; D005293:Ferritins; D007501:Iron
SLC40A1; ferroportin; hemochromatosis; hepcidin; iron overload