Erythro-megakaryocytic transcription factors associated with hereditary anemia

Abstract

Most heritable anemias are caused by mutations in genes encoding globins, red blood cell (RBC) membrane proteins, or enzymes in the glycolytic and hexose monophosphate shunt pathways. A less common class of genetic anemia is caused by mutations that alter the functions of erythroid transcription factors (TFs). Many TF mutations associated with heritable anemia cause truncations or amino acid substitutions, resulting in the production of functionally altered proteins. Characterization of these mutant proteins has provided insights into mechanisms of gene expression, hematopoietic development, and human disease. Mutations within promoter or enhancer regions that disrupt TF binding to essential erythroid genes also cause anemia and heritable variations in RBC traits, such as fetal hemoglobin content. Defining the latter may have important clinical implications for de-repressing fetal hemoglobin synthesis to treat sickle cell anemia and β thalassemia. Functionally important alterations in genes encoding TFs or their cognate cis elements are likely to occur more frequently than currently appreciated, a hypothesis that will soon be tested through ongoing genome-wide association studies and the rapidly expanding use of global genome sequencing for human diagnostics. Findings obtained through such studies of RBCs and associated diseases are likely generalizable to many human diseases and quantitative traits.

The Poly(C) Binding Protein Pcbp2 and Its Retrotransposed Derivative Pcbp1 Are Independently Essential to Mouse Development

“…The absence of apparent defects in granulocyte and monocyte lineage cell number (data not shown) suggests that Pcbp2 loss has a greater impact upon the megakaryocyte-erythrocyte progenitor (MEP) cell population. Several transcription factors regulate MEP lineage determination (KLF1 and FLI1) and maturation of erythrocytes and megakaryocytes (GATA1, TAL1, FOG1, NF-E2, and GFIIB) (86). We observed downregulation of Klf1, Tal1, and Nfe2 in Pcbp2 Ϫ/Ϫ 12.5-dpc fetal liver, which decreased 42%, 46%, and 60%, respectively ( Fig.…”

A novel 33‐Gene targeted resequencing panel provides accurate, clinical‐grade diagnosis and improves patient management for rare inherited anaemias

“…In particular, we plan to include a larger number of red cell enzyme genes and add red cell membrane genes to the panel. Furthermore, the diagnostic utility of such panels depends on a regular process of review to accommodate relevant newly identified pathogenic and modifying mutations in genes and their promoters and regulatory elements (Crispino & Weiss, 2014). It is likely that whole exome sequencing or whole genome sequencing, which provide a much more comprehensive, unbiased approach, will replace targeted sequencing in the future.…”

GATA factor mutations in hematologic disease

“…Germ line mutations of GATA1, which resides on the X chromosome, cause a variety of sex-linked recessive forms of hereditary thrombocytopenia and dyserythropoietic anemia. 3 Furthermore, acquired somatic mutations in GATA1 accompany the development of Down syndrome (DS) transient abnormal myelopoiesis, hereafter referred to as transient myeloproliferative disorder (TMD), and myeloid leukemia associated with DS, hereafter referred to as DS acute megakaryoblastic leukemia (DS-AMKL). 4,5 Germ line GATA2 mutations are responsible for GATA2 deficiency syndrome.…”