Mutations of SLC40A1 encoding ferroportin (Fpn), the unique cellular iron 
exporter, severely affect iron homeostasis causing type 4 hereditary 
hemochromatosis, an autosomal dominant iron overload condition with variable 
phenotypic manifestations. This disease can be classified as type 4A, better 
known as "ferroportin disease", which is due to "loss of function" mutations 
that lead to decreased iron export from cells, or as type 4B hemochromatosis, 
which is caused by "gain of function" mutations, conferring partial or complete 
resistance to hepcidin-mediated Fpn degradation. In this work, we discuss 
clinical and molecular findings on a group of patients in whom a SLC40A1 single 
copy missense variant was identified. Three novel variants, p.D181N, p.G204R and 
p.R296Q were functionally characterized. Fpn D181N and R296Q mutants can be 
classified as full or partial loss of function, respectively. Replacement of 
G204 with arginine appears to cause a more complex defect with impact both on 
iron export function and hepcidin sensitivity. This finding confirms the 
difficulty of predicting the effect of a mutation on the molecular properties of 
Fpn in order to provide an exhaustive explanation to the wide variability of the 
phenotype in type 4 hereditary hemochromatosis.