Twenty Years of Ferroportin Disease: A Review or An Update of Published Clinical, Biochemical, Molecular, and Functional Features.

L Tom Vlasveld,Houda Hamdi-Roze,Roel Janssen,Roel Janssen,Edouard Bardou-Jacquet,Hanka Venselaar,Hanka Venselaar,Hanka Venselaar,Hal Drakesmith,Hal Drakesmith,Dorine W Swinkels,Dorine W Swinkels

doi:10.3390/ph12030132

Abstract

Iron overloading disorders linked to mutations in ferroportin have diverse phenotypes in vivo, and the effects of mutations on ferroportin in vitro range from loss of function (LOF) to gain of function (GOF) with hepcidin resistance. We reviewed 359 patients with 60 ferroportin variants. Overall, macrophage iron overload and low/normal transferrin saturation (TSAT) segregated with mutations that caused LOF, while GOF mutations were linked to high TSAT and parenchymal iron accumulation. However, the pathogenicity of individual variants is difficult to establish due to the lack of sufficiently reported data, large inter-assay variability of functional studies, and the uncertainty associated with the performance of available in silico prediction models. Since the phenotypes of hepcidin-resistant GOF variants are indistinguishable from the other types of hereditary hemochromatosis (HH), these variants may be categorized as ferroportin-associated HH, while the entity ferroportin disease may be confined to patients with LOF variants. To further improve the management of ferroportin disease, we advocate for a global registry, with standardized clinical analysis and validation of the functional tests preferably performed in human-derived enterocytic and macrophagic cell lines. Moreover, studies are warranted to unravel the definite structure of ferroportin and the indispensable residues that are essential for functionality.

Highlights

Hereditary hemochromatosis (HH) type 4 or ferroportin disease (OMIM-code: 606069 Orphanet-code: 139491) is associated with variants in SLC40A1 and inherited in an autosomal-dominant manner
The clinical and laboratory features of the patients with these ferroportin variants were correlated with data on variant properties in functional in vitro tests, which were available for 80% of the variants
loss of function (LOF) variants are associated with macrophage iron retention with a high serum ferritin and low to normal transferrin saturation (TSAT), in contrast to gain of function (GOF) variants, which are associated with high TSAT and hepatocellular iron deposition

Summary

Introduction

Hereditary hemochromatosis (HH) type 4 or ferroportin disease (OMIM-code: 606069 Orphanet-code: 139491) is associated with variants in SLC40A1 and inherited in an autosomal-dominant manner. Classical ferroportin disease (Type 4A) is associated with loss-of-function (LOF) variants with diminished cell surface expression of ferroportin and lower iron export capacity, and is characterized by macrophage iron retention and iron restriction for erythropoiesis. It is clinically recognized by the presence of high serum ferritin concentrations with low to normal transferrin saturation (TSAT) and poor tolerance to phlebotomy. Non-classical (atypical, type 4B) ferroportin disease is associated with gain-of-function (GOF) variants that render ferroportin protein resistant to hepcidin, resulting in continued iron export, and leading to a phenotype that mimics classical HFE HH characterized by parenchymal (hepatocellular) iron overload with elevated serum ferritin and TSAT. Systematic and narrative reviews on ferroportin disease revealed the great variety in iron parameters among patients with ferroportin variants and emphasize the poor correlation between iron export capacity in functional studies and clinical characteristics (phenotype) [7,9,10,11] and question the pathogenicity of various variants [8,12]

Methods

Results

Conclusion