GATA1 mutations in red cell disorders

Abstract

GATA1 is an essential regulator of erythroid cell gene expression and maturation. In its absence, erythroid progenitors are arrested in differentiation and undergo apoptosis. Much has been learned about GATA1 function through animal models, which include genetic knockouts as well as ones with decreased levels of expression. However, even greater insights have come from the finding that a number of rare red cell disorders, including Diamond-Blackfan anemia, are associated with GATA1 mutations. These mutations affect the amino-terminal zinc finger (N-ZF) and the amino-terminus of the protein, and in both cases can alter the DNA-binding activity, which is primarily conferred by the third functional domain, the carboxyl-terminal zinc finger (C-ZF). Here we discuss the role of GATA1 in erythropoiesis with an emphasis on the mutations found in human patients with red cell disorders.

Keywords: GATA1; anemia; erythropoiesis.

Figure 1.. Schematic of the GATA1 gene and known mutations in patients with congenital erythroid disorders.

GATA1 is composed of six exons which encode two transcripts that produce the full-length isoform (upper) or the N-terminally truncated GATA1s isoform (lower). The locations of GATA1 mutations found in patients with congenital erythroid disorders are indicated along GATA1 gene. Mutations at the boundaries of exon 2 (green), mutations within the sequences that encode the N-terminal zinc finger (purple), and those within intron 5 (red) are depicted. The mutations at the boundaries of exon 2 cause splicing defects that result in the exclusive generation of GATA1s, while mutations within exon 4 create variants that attenuate the GATA1-FOG1 interaction or impair DNA binding. The g.7230C>T alteration causes a five-amino acid (PPFWQ) insertion at the C-terminus of the C-terminal zinc finger. GATA1 cofactors and their interacting domains are shown on top. N-TAD, amino-terminal trans-activation domain; N-ZF, amino-terminal zinc finger; C-ZF, carboxyl-terminal zinc finger.

Figure 2.. Mechanisms that lead to Diamond-Blackfan anemia.

The majority of germline mutations found in DBA patients reside in ribosome protein (RP) coding genes. The resulting RP haploinsufficiency leads to inefficient translation of a number of erythroid genes, such as globin and GATA1, resulting in impaired erythropoiesis. Moreover, free ribosomal subunits, such as RPL5 and RPL23, block MDM2-mediated P53 ubiquitination and degradation, leading an increase of P53-dependent apoptosis of the erythroid progenitors. In other patients, GATA1 gene mutations result in loss of the full-length protein but allow for expression of the shorter isoform (GATA1s mutations), which also impairs erythropoiesis. Finally, an altered globin-heme balance has been shown to lead to the accumulation of free heme in cytoplasm, which downregulates GATA1 at both the mRNA and protein level. FLVCR1a and FLVCR1b are heme transporters on cell membrane and mitochondrial membrane respectively.