Clinical, pathological, and molecular correlates in ferroportin disease: a study of two novel mutations

Area of Science:

• Genetics and Molecular Biology
• Hematology
• Cell Biology

Background:

• Ferroportin (Fpn) disease (FD) presents with varied clinical and pathological manifestations, including iron overload predominantly in macrophages (M phenotype) or hepatocytes (H phenotype).
• This phenotypic heterogeneity is thought to stem from functional differences among ferroportin mutants.
• Loss-of-function mutations typically result in the M phenotype.

Observation:

• Two unrelated patients with non-HFE hemochromatosis were screened for Fpn mutations, revealing two novel mutations: I152F and L233P.
• The I152F mutation, found in a patient with the M phenotype, demonstrated a primary defect in iron export.
• The L233P mutation, associated with ambiguous overload in both macrophages and hepatocytes, showed improper cell surface trafficking.

Findings:

• Both novel Fpn mutations (I152F and L233P) were functionally characterized and confirmed to be loss-of-function.
• In vitro studies showed I152F has a direct iron export deficit, while L233P exhibits trafficking defects.
• In vivo studies using zebrafish models confirmed loss of function, leading to iron-limited erythropoiesis.

Implications:

• Understanding Fpn mutant function is crucial for explaining the diverse clinical presentations of ferroportin disease.
• Combined clinico-pathological and molecular analysis provides robust explanations for FD phenotype heterogeneity.
• These findings advance the understanding of iron metabolism disorders and potential therapeutic targets.