SLC40A1 – Hereditary Hemochromatosis

Autosomal dominant mutations in SLC40A1, encoding the iron export protein ferroportin, cause type 4 hereditary hemochromatosis (HH), a phenotypically heterogeneous iron overload disorder distinct from classical HFE-related HH. Patients typically present with hyperferritinemia, variable transferrin saturation, and hepatic iron deposition with or without macrophage involvement.

Genetic evidence derives from multiple independent pedigrees reporting missense and splice-site variants. To date, over 20 probands across at least eight unrelated families have been described with SLC40A1 variants co-segregating with HH (PMID:15727899; PMID:28930842). These include classic missense mutations (e.g., c.977G>T (p.Cys326Phe)) and noncanonical splicing defects (IVS3+10delGTT).

Inheritance is autosomal dominant, with co-segregation observed in 15 affected relatives from multigenerational kindreds (PMID:15727899). This robust familial segregation, combined with recurrent identification of key variants in diverse populations (Poland, Japan, China, Spain), supports a definitive gene-disease association.

The SLC40A1 variant spectrum includes >10 distinct missense changes clustered in extracellular loops and transmembrane domains, plus rare splice and deletion alleles. The recurrent c.977G>T (p.Cys326Phe) variant underlies early‐onset HH with hepatocyte iron loading (PMID:15727899).

Functional assays demonstrate that ferroportin forms multimers (PMID:15956209) and that pathogenic mutants exhibit either loss-of-function (e.g., A77D impairs iron export; PMID:15692071) or gain-of-function via hepcidin resistance (e.g., Cys326Tyr remains surface-localized despite hepcidin; PMID:15831700). In vivo, the Pcm mouse model with dysregulated ferroportin expression recapitulates polycythemia and anemia phenotypes (PMID:15084469).

These data delineate dual mechanisms—haploinsufficiency and impaired hepcidin responsiveness—driving SLC40A1-mediated HH. No studies have refuted the association, and phenotypic variability likely reflects both variant‐specific effects and modifying factors.

Integration of genetic and functional findings confirms that SLC40A1 variants cause dominantly inherited iron overload with spectrum ranging from macrophage‐predominant to parenchymal deposition. Routine SLC40A1 testing is recommended in non-HFE HH cases, informing early intervention with phlebotomy or chelation.

Key Take-home: Definitive evidence supports SLC40A1 as a clinically actionable AD HH gene amenable to targeted genetic testing for diagnosis and management.

References

• Blood cells, molecules & diseases • 2005 • Autosomal dominant hereditary hemochromatosis associated with a novel ferroportin mutation and unique clinical features. PMID:15727899
• Proceedings of the National Academy of Sciences • 2005 • The molecular basis of ferroportin-linked hemochromatosis. PMID:15956209
• Blood • 2005 • In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations. PMID:15692071
• Blood • 2005 • Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. PMID:15831700
• Development (Cambridge, England) • 2004 • Disruption of ferroportin 1 regulation causes dynamic alterations in iron homeostasis and erythropoiesis in polycythaemia mice. PMID:15084469

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