STEAP3, also called TSAP6, was first reported in relation to autosomal dominant severe congenital hypochromic anemia with ringed sideroblasts in 2011 (Grandchamp B et al., PMID:22031863). The index family from the original report presented with transfusion-dependent, poorly regenerative anemia and iron overload with onset in early childhood asserted to be caused by a premature termination in STEAP3 (p.Cys110Ter); the affected siblings also inherited a lowly expressed hypomorphic allele. In a 2015 report by Liu et al. (PMID:26675350) 33 heterozygotes carrying an early termination variant (p.Cys271Ter) were identified and none of them had any significant erythrocyte hematologic phenotype. This report also includes a family where the mother has a missense STEAP3 variant and no phenotype, the father has a missense variant predicted to be a null variant after transfection in HeLa cells showed completely abrogated iron reduction but has no hematologic phenotype and the couple’s child carries both variants in a compound heterozygous state and has no hematologic phenotype.
This gene-disease relationship is supported by expression studies, biochemical function assays and animal models. RNA-seq performed on 27 tissues from 95 individuals shows specific expression of STEAP3 in the liver (PMID:24309898). Overexpression of STEAP3 by plasmids in HEK-293T cells showed the ferrireductase activity of STEAP3 (PMID:16609065). Lespagnol A et al. created a TSAP6 knockdown mouse model where the mice presented with microcytic, hypochromic anemia (PMID:18617898). A mouse model (nm1054) known to have microcytic, hypochromic anemia was investigated and found to have STEAP3 through a positional cloning approach. Ferrireductase activity was measured in reticulocytes harvested from the mice. Both mutant and null cells were both found to have reduced activity as compared to the wild-type (PMID:16227996).
In summary, the evidence supporting the relationship between STEAP3 and autosomal dominant severe congenital hypochromic anemia has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role STEAP3 plays in this disease. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on the meeting date 25 April, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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