SPLICING ERROR IN GATA1 AFFECTS ERYTHROPOIESIS IN THE XPNA MOUSE (X-LINKED PRE- AND NEONATAL ANEMIA) WITH SUGGESTION OF A NOVEL COMPENSATORY ERYTHROID TRANSCRIPTION FACTOR

Abstract

A novel mutant mouse called X-linked pre- and neonatal anemia (gene symbol, Xpna) results in a transient, neonatal anemia which is resolved by 3 weeks of age in Xpna females. Adult Xpna females exhibit hypoplastic bone marrow with red cell aplasia and splenomegaly showing extramedullary erythropoiesis and megakaryocytosis. We identified a splicing defect derived from a single nucleotide change 5 base pairs downstream of Exon 1 in Gata1. The Xpna Gata1 gene produces a transcript, which includes alternative Exon 1Eb/c, known not to induce erythropoiesis. X-chromosome inactivation leads to two populations of hematopoietic cells in Xpna females, one of which expresses Xpna Gata1 mRNA. An X-chromosome-associated erythroid genetic marker (Pgk1, phosphoglycerate kinase-1) indicates reticulocytes are derived from erythropoietic cells expressing the Xpna Gata1 transcript. These data strongly suggest compensatory gene expression allowing for the generation of erythrocytes despite the lack of GATA-1 production. The Xpna mouse could, therefore, lead to the identification of novel erythropoietic factors.