QSOX2 Deficiency-induced short stature, gastrointestinal dysmotility and immune dysfunction

Abstract Postnatal growth failure is often attributed to dysregulated somatotropin action, however marked genetic and phenotypic heterogeneity exist. We report four patients from two families who present with short stature, immune dysfunction, atopic eczema and gut-associated pathology associated with recessive variants in QSOX2 . QSOX2 encodes a nuclear membrane protein linked to disulphide isomerase and oxidoreductase activity. Loss of QSOX2 disrupts GH-mediated STAT5B nuclear translocation despite enhanced GH-induced STAT5B phosphorylation. Moreover, patient-derived dermal fibroblasts demonstrate novel GH-induced mitochondriopathy and reduced mitochondrial membrane potential. We describe a definitive role of QSOX2 in modulating human growth likely due to impairment of STAT5B downstream activity and mitochondrial dynamics leading to growth failure, immune dysregulation and gut dysfunction. Located at the nuclear membrane, QSOX2 acts as a gatekeeper for regulating stabilisation and import of p-STAT5B. Furthermore, our work suggests that therapeutic recombinant IGF-1 may circumvent the GH-mediated STAT5B molecular defect and potentially alleviate organ specific disease.