In addition, as excessive heme could amplify ribosomal protein imbalance, prematurely lower GATA1, and impede mitosis, these data may help explain the ineffective (early termination of) erythropoiesis in Diamond Blackfan anemia and del(5q) myelodysplasia, disorders with excessive heme in colony-forming unit-erythroid/proerythroblasts, explain why these anemias are macrocytic, and show why children with GATA1 mutations have DBA-like clinical phenotypes.
Substitution mutations in GATA1-Nf, such as GATA1(V205M) that diminish the GATA1-FOG1 association, have been identified in human thrombocytopenia and anemia cases.
We earlier reported on a mouse model that constitutive expression of EVI1 in the BM led to fatal anemia and myeloid dysplasia, as observed in MDS patients, and we subsequently showed that EVI1 interaction with GATA1 blocks proper erythropoiesis.
Several transcription factors regulating haematopoiesis, Tal1, Gata1, Zfpm1 and Klf1 were expressed at consistently lower levels in C57BL/6 mice suggesting that these mice have a lower haematopoietic capacity and therefore less ability to recover from haemolysis induced anaemia after infection.
These five human diseases are: X-linked thrombocytopenia (XLT), X-linked thrombocytopenia with thalassemia (XLTT), congenital erythropoietic porphyria (CEP), transient myeloproliferative disorder (TMD) and acute megarakaryoblastic leukemia (AMKL) associated with Trisomy 21, and, lastly, a particular subtype of anemia associated with the production of GATA-1s, a shortened, mutant isoform of the wild-type GATA-1.
To date, mutations of GATA-1 gene have been found in inherited anemia and thrombocytopenia, and Down syndrome-related acute leukemia, which exhibits megakaryocytic phenotypes and frequently occurs in patients with Down syndrome.
In high-expressor lines we observed that the GATA-1(V205G) rescues GATA-1-deficient mice from embryonic lethality at the expected frequency, revealing that excess GATA-1(V205G) can eliminate the lethal anemia that is due to GATA-1 deficiency.
Missense mutations in the N-terminal zinc finger (Nf) of GATA1 result in abnormal hematopoiesis, as documented in four families: the mutation V205M leads to both severe macrothrombocytopenia and dyserythropoietic anemia, D218G to macrothrombocytopenia and mild dyserythropoiesis without anemia, G208S to macrothrombocytopenia and R216Q to macrothrombocytopenia with beta-thalassemia.
In this study, we describe a new family with deep macrothrombocytopenia, marked anemia and early mortality, if untreated, due to a different GATA1 mutation (D218Y) in the same residue 218 also implicated in the above mentioned milder phenotype.
Here we describe a family with X-linked dyserythropoietic anaemia and thrombocytopenia due to a substitution of methionine for valine at amino acid 205 of GATA-1.