SLC40A1 – Hemochromatosis Type 1

Heterozygous variants in SLC40A1 have been reported in a small number of patients presenting with a classical hemochromatosis type 1 phenotype characterized by hyperferritinaemia and transferrin saturation elevation. In a Spanish man with hyperferritinaemia and facial flushing, molecular analysis identified double heterozygosity for the HFE c.-20G>A variant and SLC40A1 c.718A>G (p.Lys240Glu), with phlebotomy ameliorating iron overload (PMID:21175851). A Japanese patient with iron overload but no HFE, TFR2, HAMP, or HJV coding mutations harboured a novel noncoding SLC40A1 A>G substitution 7 nucleotides downstream of the IRE, absent in 50 controls, suggesting a possible pathogenic role (PMID:15897636).

The inheritance pattern is autosomal dominant, but segregation is poorly documented, with no additional affected relatives reported. Only three unrelated probands have been described, and no multi-family segregation or replication studies have validated SLC40A1 as a causative gene for MONDO:0021001. Functional assays of ferroportin variants predominantly address type 4 disease, and no experiments to date directly link SLC40A1 variants to classical HFE-type hemochromatosis phenotypes.

Key take-home: Current evidence is insufficient to support routine clinical testing of SLC40A1 in hemochromatosis type 1 outside research settings.

References

• Internal medicine (Tokyo, Japan) • 2005 • Hemochromatosis with mutation of the ferroportin 1 (IREG1) gene PMID:15897636
• European journal of haematology • 2011 • Two novel mutations in the SLC40A1 and HFE genes implicated in iron overload in a Spanish man PMID:21175851

Evidence Based Scoring (AI generated)