SLC40A1 – Ferroportin Disease (Hemochromatosis Type 4)

Ferroportin disease, also known as hemochromatosis type 4, is an autosomal dominant iron‐overload disorder caused by heterozygous mutations in SLC40A1, the sole cellular iron exporter (ferroportin). Affected individuals exhibit hyperferritinemia (HP:0003281) with inappropriately low to normal transferrin saturation and preferential iron deposition in macrophages and Kupffer cells. The condition manifests clinically with elevated serum ferritin from adolescence onward and variable organ iron loading without overt fibrosis in many cases (V162del family)(PMID:15986403).

Genetic evidence includes over 70 affected subjects from 33 independent families segregating 19 distinct SLC40A1 variants, confirming autosomal dominant inheritance and co-segregation with iron overload phenotypes (PMID:21199650). Case reports and series document at least 30 missense mutations, multiple in‐frame deletions, and splice-site changes. A recurrent founder allele, c.485_487del (p.Val162del), has been described in several populations and co-segregates with macrophage iron retention and hyperferritinemia (PMID:15986403).

Functional assays demonstrate two mechanistic classes: loss-of-function variants impair iron egress from enterocytes and macrophages, while gain-of-function mutations confer hepcidin resistance, leading to parenchymal iron overload. Mouse Pcm models harboring promoter deletions recapitulate polycythemia and transient anemia, highlighting regulatory control by hepcidin (PMID:15084469). In vitro studies of 18 missense variants, including Gly80Cys, Ile351Val, and Gly490Asp, confirm distinct effects on cell-surface expression, iron export, and hepcidin-mediated internalization, correlating with clinical heterogeneity (PMID:24714983).

Genotype–phenotype correlations are influenced by variant class: 'M'‐phenotype mutations (e.g., V162del, A77D) predominantly cause macrophage iron loading, whereas 'H'-phenotype or hemochromatosis type 4B alleles (e.g., Y333H) resist hepcidin and promote parenchymal deposition. Incomplete penetrance and acquired cofactors modulate severity, with transferrin saturation serving as a biomarker of fibrosis risk (PMID:21199650).

No significant refuting evidence has been reported, and the large number of unrelated probands, robust segregation, and concordant functional data support a definitive gene‐disease relationship. Additional variants and regulatory elements continue to be characterized, expanding the mutational spectrum beyond classical coding changes.

Key Take-home: SLC40A1‐related ferroportin disease is a definitively established autosomal dominant disorder; molecular diagnosis enables targeted management through phlebotomy or chelation and informs family screening protocols.

References

• Hepatology • 2005 • Primary iron overload with inappropriate hepcidin expression in V162del ferroportin disease. PMID:15986403
• Gastroenterology • 2011 • Sex and acquired cofactors determine phenotypes of ferroportin disease. PMID:21199650
• Human molecular genetics • 2014 • Comprehensive functional annotation of 18 missense mutations found in suspected hemochromatosis type 4 patients. PMID:24714983
• Development • 2004 • Disruption of ferroportin 1 regulation causes dynamic alterations in iron homeostasis and erythropoiesis in polycythaemia mice. PMID:15084469
• Proceedings of the National Academy of Sciences of the United States of America • 2005 • The molecular basis of ferroportin-linked hemochromatosis. PMID:15956209

Evidence Based Scoring (AI generated)