A novel type of congenital hypochromic anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene.
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.
Assistance Publique des Hôpitaux de Paris, Hôpital Bichat, Laboratoire de Biochimie Hormonale et Génétique, Paris, France. bernard.grandchamp@bch.aphp.fr.
Bernard
B
Grandchamp
Gilles
G
Hetet
Caroline
C
Kannengiesser
Claire
C
Oudin
Carole
C
Beaumont
Sylvie
S
Rodrigues-Ferreira
Robert
R
Amson
Adam
A
Telerman
Peter
P
Nielsen
Elisabeth
E
Kohne
Christina
C
Balser
Hermann
H
Heimpel
D000293:Adolescent; D000747:Anemia, Hypochromic / Q000097:blood / Q000151:congenital / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002648:Child; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D010088:Oxidoreductases; D010375:Pedigree; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; D008565:Membrane Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; D010088:Oxidoreductases; C486677:STEAP3 protein, human; C473329:TSAP6 protein, mouse