Peroxiredoxin II (PRDX2) Is a Novel Candidate Gene for Congenital Dyserythropoietic Anemia

CDAR (ClinicalTrials.gov Identifier: NCT02964494), a registry for patients with Congenital Dyserythropoietic Anemia (CDA) in North America, has been created with the goal to provide a longitudinal database and associated biorepository to facilitate natural history studies and research on the molecular pathways involved in the pathogenesis of CDAs. A 1 y.o. female patient with non-immune hemolytic anemia with suboptimal reticulocytosis, requiring frequent transfusions, and with the pathologic diagnosis of CDA was enrolled in CDAR. Her father had a similar phenotypical presentation in early childhood and underwent splenectomy at 3 years of age. Since then, he has rarely required transfusions but he continues to have a mild anemia at baseline with characteristics of hemolysis and with suboptimal reticulocytosis; at the time of enrollment, he had hemoglobin of 9.3 g/dL with absolute reticulocyte count of 115 x 106 cells/µl. Next Generation sequencing and deletion/duplication assay for the known CDA-associated genes (CDAN1, C15ORF41, SEC23B, KIF23, GATA1) identified no mutations. Whole-exome sequencing for the patient and her parents (family-trio design) revealed a novel PRDX2 missense variant (c.154C>T; p.Pro52Ser) present in heterozygous state in both proband and her father; no mutation in this gene was present in the asymptomatic mother. In silico prediction programs suggest that this variant is probably damaging and deleterious, causing a non-conservative substitution of a phylogenetically highly-conserved amino acid (down to Baker's yeast), and located in an enzymatically active protein domain, adjacent to the active Cys51, with the potential to change its conformation. Peroxiredoxin II is highly expressed during terminal erythropoiesis and is one of the most abundant proteins after hemoglobin in erythroblasts and mature erythrocytes. It is an antioxidant enzyme that reduces the reactive oxygen species (ROS), like hydrogen peroxide and alkyl hydroperoxides readily produced within the erythroid cells due to the presence of heme iron and oxygen. In addition, PRDX2 has been implicated in intracellular signaling, cellular proliferation and differentiation, and as a regulator of iron homeostasis. PRDX2-/- mice were found to have hemolytic anemia with evidence of oxidative damage of the erythrocyte proteins resulting to decreased red blood cell (RBC) survival. The aim of this work is to validate the pathogenetic role of the PRDX2 variant found in this family as