Single-cell RNA-seq analysis of bone marrow cells from a RABGGTA-deficient patient and pediatric controls

Protein prenylation is essential for membrane targeting of signaling and trafficking proteins. We identified a recurrent homozygous RABGGTA missense variant (L235F) in 23 patients from 19 consanguineous families with a severe multisystem disorder characterized by bicytopenia, recurrent infections, systemic inflammation, and life-threatening bleeding. The variant destabilized Rab geranylgeranyltransferase, resulting in widespread Rab hypoprenylation, mislocalization, and defective vesicular trafficking. RABGGTA deficiency impaired megakaryocyte maturation, platelet granule biogenesis and aggregation, as well as cytotoxic lymphocyte function, leading to macrothrombocytopenia and HLH-like inflammation. Transcriptomic and proteomic analyses revealed broad dysregulation of vesicular trafficking and stress-response pathways. Complete Rabggta loss was embryonic lethal in mice, whereas hypomorphic gunmetal mice recapitulated key hematologic and inflammatory features of the human disease. RABGGTA deficiency therefore defines the first Mendelian disorder of protein prenyltransferase function in humans and reveals Rab prenylation as a critical regulator of platelet and immune homeostasis. The present dataset corresponds to single-cell RNA sequencing of bone marrow mononuclear cells from patient P20 and two healthy pediatric controls.