Abstract
The emergence of next-generation sequencing techniques has led to the genetic characterization of numerous congenital erythroid disorders, emphasizing crucial pathways in both normal and pathological erythropoiesis. In this study, whole exome sequencing of a single patient with atypical congenital pure red cell aplasia revealed a mutation in the CDAN1 gene, typically associated with congenital dyserythropoietic anemia type 1 (CDAI), together with a previously unreported mutation in the MMS22L gene. Combined mms22l and cdan1 haploinsufficiency results in severe anemia in a zebrafish model. In human erythroid progenitors, loss of MMS22L leads to proliferation and differentiation arrest associated with activation of the p53 pathway and global epigenetic alterations, showing that MMS22L plays an indispensable role in erythropoiesis. Furthermore, MMS22L and CDAN1 are involved in the same protein complex whose nuclear import is mediated by the importin 4 (IPO4) protein, and MMS22L nuclear import is impaired in CDAI patients due to a defective interaction between CDAN1 and IPO4. Overall, through the genetic description of a single case characterized by digenic inheritance, we identified MMS22L as a novel key factor in erythropoiesis and brought new insights into normal erythropoiesis regulation and CDAI pathophysiology.