[5][7] In consequence of the vital role that GATA1 has in the proper maturation of red blood cells and platelets, inactivating mutations in the GATA1 gene (i.e. mutations that result in the production of no, reduced levels of, or a less active GATA1) cause X chromosome-linked anemic and/or bleeding diseases due to the reduced formation and functionality of red blood cells and/or platelets, respectively, or, under certain circumstances, the pathological proliferation of megakaryoblasts.

[8][9][10] Reduced levels of GATA1 due to reductions in the translation of GATA1 mRNA into its transcription factor product are associated with promoting the progression of myelofibrosis, i.e. a malignant disease that involves the replacement of bone marrow cells by fibrous tissue and extramedullary hematopoiesis, i.e. the extension of blood cell-forming cells to sites outside of the bone marrow.

Apparently, the GATA2 gene's expression level must be delicately balanced between deficiency and excess in order to avoid life-threatening disease.

GATA1-inactivating mutations may thereby result in a failure to produce sufficient numbers of and/or fully functional red blood cells.

[5][7] Reduced levels of GATA1 due to defective translation of GATA1 mRNA in human megakaryocytes is associated with myelofibrosis, i.e. the replacement of bone marrow cells by fibrous tissue.

Based on mouse studies, low GATA1 levels are also thought to promote the development of splenic enlargement and extramedullary hematopoiesis in human myelofibrosis disease.

For example, mutations in GATA1's N-ZnF that interfere with its interaction with FOG1 result in reduced red blood cell and platelet levels whereas mutations in N-ZnF that reduce its binding affinity to target genes cause a reduction in red blood cells plus thalassemia-type and porphyria-type symptoms.

[8] Acquired inactivating mutations in the activation domain of GATA1 are the apparent cause of the transient myeloproliferative disorder that occurs in individuals with Down syndrome.

These mutations are frameshifts in exon 2 that result in the failure to make GATA1 protein, continued formation of GATA1-S, and therefore a greatly reduced ability to regulate GATA1-targeted genes.

It resolves totally within ~3 months but in the following 1–3 years progresses to acute megakaryoblastic leukemia in 20% to 30% of these individuals: transient myeloprolierative disorder is a clonal (abnormal cells derived from single parent cells), pre-leukemic condition and is classified as a myelodysplastic syndrome disease.

Their GATA1 mutations are frameshifts in exon 2 that result in the failure to make GATA1 protein, continued formation of GATA1-S, and thus a greatly reduced ability to regulate GATA1-targeted genes.

Transient myeloproliferative disorder is detected at or soon after birth and generally resolves during the next months but is followed within 1–3 years by acute megakaryoblastic leukemia.

In virtually all the remaining cases, autosomal recessive inactivating mutations occur in any one of 20 of the 80 genes encoding ribosomal proteins.

These GATA1 mutations occur in an exon 2 splice site or the start codon of GATA1, cause the production of the GATA1-S in the absence of the GATA1 transcription factor, and therefore are gene-inactivating in nature.

[8][15][16] Certain GATA1-inactivatng mutations are associated with familial or, less commonly, sporadic X-linked disorders that consist of anemia and thrombocytopenia due to a failure in the maturation of red blood cell and platelet precursors plus other hematological abnormalities.

The syndrome is commonly considered to result solely from mutations in the NBEAL2 gene located on human chromosome 3 at position p21.

In these cases, the syndrome follows autosomal recessive inheritance, causes a mild to moderate bleeding tendency, and may be accompanied by a defect in the secretion of the granule contents in neutrophils.

The GATA1 mutation-related disease resembles the one caused by NBEAL2 mutations in that it is associated with the circulation of a reduced number (i.e. thrombocytopenia) of abnormally enlarged (i.e. macrothrombocytes), alpha-granule deficient platelets.

Recent studies indicate that the megakaryocytes but not other cell types in rare cases of myelofibrosis have greatly reduced levels of GATA1 as a result of a ribosomal deficiency in translating GATA1 mRNA into GATA1 transcription factor.