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

• Published in: Blood 2011-12, Vol.118 (25), p.6660-6666
• Main Authors: Grandchamp, Bernard, Hetet, Gilles, Kannengiesser, Caroline, Oudin, Claire, Beaumont, Carole, Rodrigues-Ferreira, Sylvie, Amson, Robert, Telerman, Adam, Nielsen, Peter, Kohne, Elisabeth, Balser, Christina, Heimpel, Hermann
• Format: Article
• Language: English
• Subjects: Adolescent; Anemia, Hypochromic - blood; Anemia, Hypochromic - congenital; Anemia, Hypochromic - genetics; Anemias. Hemoglobinopathies; Animals; Biochemistry, Molecular Biology; Biological and medical sciences; Blotting, Western; Cell Cycle Proteins; Cell Line, Transformed; Cells, Cultured; Cellular Biology; Child; Codon, Nonsense; Diseases of red blood cells; DNA Mutational Analysis; Embryo, Mammalian - cytology; Embryo, Mammalian - metabolism; Family Health; Female; Fibroblasts - cytology; Fibroblasts - metabolism; Gene Expression; Genetics; Hematologic and hematopoietic diseases; Human health and pathology; Humans; Life Sciences; Male; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Oxidoreductases; Pedigree; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - blood; RNA, Messenger - genetics; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-01-329011

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.