GATA1 and KLF1 domain modules, mutations, and associated diseases. (A) (Top) Three domains of GATA1 are shown: the N and C-terminal zinc fingers (Nf and Cf) and the NAD. (Middle) Mutations in the Nf (noted by asterisks) disrupt DNA binding or associations with the essential cofactors Friend of GATA1 (FOG-1) or TAL1 complex. These germ-line mutations cause a variety of inherited anemias and/or thrombocytopenias. (Bottom) Distinct mutations within exon 2 lead to predominant expression of GATA1s, which retains both zinc fingers, but is missing the NAD. In infants and young children with DS (trisomy 21), somatic mutations that favor GATA1s production cause TMD and AMKL. In euploid patients, germ-line GATA1s mutations are associated with congenital anemia, including DBA. (B) KLF1 includes an N-terminal proline-rich domain and 3 C-terminal zinc finger domains. Various missense and frameshift mutations (noted by asterisks) throughout the gene are associated with hereditary anemias, altered Lutheran blood group expression, and/or persistence of fetal hemoglobin expression. Note that E325K has a dominant negative effect. Adapted from Singleton et al.⁵⁸