SLC11A2 – Microcytic Anemia with Liver Iron Overload

Biallelic mutations in the SLC11A2 gene cause an ultra-rare autosomal recessive microcytic anemia with hepatic iron overload (microcytic anemia with liver iron overload). DMT1, the divalent metal transporter 1, mediates Fe²⁺ uptake across the apical membrane of enterocytes and from transferrin-containing endosomes into the cytosol, maintaining systemic iron homeostasis.

Two novel cases expand the genetic spectrum of this disorder. The first proband is homozygous for a splicing variant c.675+35A>G, with minigene assays confirming aberrant exon retention and loss of transporter function ([PMID:35457224]). The second proband harbors homozygous c.223G>C (p.Gly75Arg), which causes improper DMT1 lysosomal accumulation and markedly reduced protein levels in HuTu 80 cells and patient lymphoblasts ([PMID:35457224]). Combined with eight previously published patients, there are now 10 unrelated probands, supporting autosomal recessive inheritance ([PMID:35457224]).

Animal models corroborate the human phenotype. Homozygous mk/mk mice carrying the orthologous G185R mutation exhibit microcytic, hypochromic anemia due to severe defects in intestinal iron absorption and erythroid iron utilization ([PMID:9241278]). Belgrade rats with the same G185R change show impaired endosomal iron egress and gastrointestinal uptake, confirming that G185R disrupts Nramp2 function ([PMID:9448300]). In vitro site-directed mutagenesis of G185R demonstrates near-total loss of iron transport, independent of protein degradation ([PMID:9731075]).

Patient‐derived cells with p.Gly75Arg exhibit mislocalization of DMT1 to lysosomes, reduced steady-state levels, and diminished Fe²⁺ uptake, mirroring the rodent findings ([PMID:35457224]). Recombinant erythropoietin therapy improves hemoglobin levels and may facilitate mobilization of hepatic iron, offering a targeted management strategy.

The pathogenic mechanism is loss of function through impaired trafficking, increased proteasomal degradation, and defective metal translocation. Genetic testing for SLC11A2 variants is warranted in congenital microcytic anemia with paradoxical liver iron overload. Functional assays can guide diagnostic confirmation and therapeutic planning.

Key Take-home: Bi-allelic SLC11A2 mutations cause autosomal recessive microcytic anemia with hepatic iron overload; strong genetic and functional data support inclusion in diagnostic panels and inform personalized management.

References

• International journal of molecular sciences • 2022 • New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation. PMID:35457224
• Nature genetics • 1997 • Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. PMID:9241278
• Proceedings of the National Academy of Sciences of the United States of America • 1998 • Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. PMID:9448300
• Blood • 1998 • The G185R mutation disrupts function of the iron transporter Nramp2. PMID:9731075

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