The Spectra of Disease-Causing Mutations in the Ferroportin 1 (SLC40A1) Encoding Gene and Related Iron Overload Phenotypes (Hemochromatosis Type 4 and Ferroportin Disease)

Abstract

SLC40A1 is the sole iron export protein reported in mammals and is a key player in both cellular and systemic iron homeostasis. This unique iron exporter, which belongs to the major facilitator superfamily, is predominantly regulated by the hyposideremic hormone hepcidin. SLC40A1 dysfunction causes ferroportin disease, and autosomal dominant iron overload disorder characterized by cellular iron retention, principally in reticuloendothelial cells, correlating with high serum ferritin and low to normal transferrin saturation. Resistant to hepcidin, SLC40A1 mutations are rather associated with elevated plasma iron and parenchymal iron deposition, a condition that resembles HFE-related hemochromatosis and is associated with more clinical complications. With very few exceptions, only missense variations are reported at the SLC40A1 locus; this situation increasingly limits the establishment of pathogenicity. In this mutation update, we provide a comprehensive review of all the pathogenic or likely pathogenic variants, variants of unknown significance, and benign or likely benign SLC40A1 variants. The classification is essentially determined using functional, structural, segregation, and recurrence data. We furnish new information on genotype-phenotype correlations for loss-of-function, gain-of-function, and other SLC40A1 variants, confirming the existence of wide clinical heterogeneity and the potential for misdiagnosis. All information is recorded in a locus-specific online database.

Insights into the role of glycerophospholipids on the iron export function of SLC40A1 and the molecular mechanisms of ferroportin disease

“…Its behavior is similar to that of the recurrent p.Arg178Gln mutation (16). This completes our previous findings (8,13,16,34,42,43), pointing that the loss of a basic side chain in the cytosolic part of transmembrane helix 5, in the vicinity of the SLC40A1 inner gate and in contact with lipids, may also be responsible for FD.…”

“…Serum ferritin level at diagnostic was 819 µL, contrasting with normal transferrin saturation (39%). We previously classify this amino acid change as a variant of unknown significance, asking for further clinical, functional or structural data (8). We here demonstrate that it reduces the SLC40A1 iron export function, and thus corresponds to a new loss-of-function mutation.…”

“…In vitro evaluation of the p.Arg179Thr substitution, currently classified as a variant of unknown significance We very recently examined the clinical significance of virtually all the missense variations reported in the SLC40A1 gene in literature, taking into account all available phenotypic, familial and functional data (8). We classified the p.Arg179Thr substitution as a variant of unknown significance, as it has been reported in single patient (or Italian origin) without evidence of tissue iron overload (19).…”

“…The authors confirmed the critical role of intra- and inter-lobe ion-pair interactions for inner gate stability, and a consistent involvement in conformational transitions between different states. We also pointed out the importance of gating residues in understanding the molecular mechanisms of FD (13), with a particular focus on the p.Arg178Gln missense mutation which breaks an important inter-domain salt bridge between Arg178 (TM5) and Asp157 (TM10) and is probably the most common disease-causing mutation reported to date (8, 16).…”

“…This 62,5 kDa multipass plasma membrane protein, which is notably expressed in reticuloendothelial macrophages, duodenal enterocytes, hepatocytes, placenta syncytiotrophoblasts and erythrocytes, is the only mammalian iron exporter (1)(2)(3)(4)(5). Its dysfunction is responsible for Ferroportin Disease (FD), an inborn error of iron metabolism transmitted as an autosomal dominant trait and observed in different ethnic groups (6)(7)(8).…”