A novel type of congenital hypochromic anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene

Abstract

STEAP3/TSAP6 encodes a ferrireductase that is involved in the acquisition of iron by developing erythroblasts and steap3/ tsap6 null-mice display severe microcytic anemia. We report a family in which 3 siblings born to healthy parents display transfusion-dependent hypochromic anemia. A nonsense STEAP3/TSAP6 was identified in the siblings at the heterozygous state. This mutation was inherited from their father while no mutation was found in their mother. A large variability of expression was found between normal alleles in a control population, confirming a previous report that STEAP3/TSAPS6 is an expressed quantitative trait locus (e-QTL). Determination of the relative allele expression showed that the "normal" allele was expressed at a significantly higher level in the father than in the affected siblings relative to the shared mutated allele. The blood level of STEAP3/ TSAP6 mRNA was severely reduced in the siblings, while both parents were in the lower range of normal controls. The STEAP3/TSAP6 protein was also reduced in lymphocytic cell lines from the patients. Collectively, our data support the hypothesis that STEAP3/TSAP6 deficiency leads to severe anemia in the affected siblings and results from the combination of a mutated allele inherited from their father and a weakly expressed allele inherited from their mother. (Blood. 2011;118(25):6660-6666)

Iron refractory iron deficiency anemia

“…58,59 The association between a deleterious mutation and a low expressed allele has been found in several inherited disorders such as erythropoietic protoporphyria, 60 spherocytosis 61 or microcytic anemia due to STEAP3 mutations. 62 This might be a rather frequent situation since recent reports have demonstrated that preferential/specific allele expression may concern 5-20% of the genes. 63,64 Finally, hypomorphic TMPRSS6 alleles have been found to contribute to the IRIDA phenotype, despite an apparent normal biological activity in functional in vitro assay.…”

Metalloreductase Steap3 coordinates the regulation of iron homeostasis and inflammatory responses

“…12 Recently, a nonsense mutation in the Steap3 gene was found to be associated with a novel type of congenital hypochromic anemia. 13 Here we demonstrate that Steap3 is the only STEAP family member highly expressed in macrophages, a cell population that functions in innate immunity. The functional characteristics illustrate the crucial roles played by macrophages in both modulation of iron homeostasis and immune responses.…”

The Crystal Structure of Six-transmembrane Epithelial Antigen of the Prostate 4 (Steap4), a Ferri/Cuprireductase, Suggests a Novel Interdomain Flavin-binding Site

“…It serves as the major ferric reductase of the transferrin cycle, where it reduces endosomal Fe 3ϩ to Fe 2ϩ , which is then transported across the endosomal membrane by DMT-1 (divalent metal transporter-1) (2, 8 -10). Accordingly, the Steap3 Ϫ/Ϫ mouse exhibits microcytic, hypochromic anemia (2), and a similar phenotype has been linked to low STEAP3 expression in humans (11).…”