When protein targeting fails: SRP pathway and hematopoietic disorders

The signal recognition particle (SRP) and SEC61 translocon coordinate co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum, a process that is increasingly recognized as critical for normal granulopoiesis and bone marrow function. Germline mutations in SRP subunits, the SRP receptor, and SEC61 define a group of severe congenital neutropenia and inherited bone marrow failure syndromes driven by disrupted protein targeting and ER homeostasis. In this review, we summarize the structural and mechanistic consequences of these mutations, connect them to characteristic clinical phenotypes, and highlight emerging concepts and open questions that will shape diagnosis and therapy for SRP‑related disorders.