biostudies-literatureMaharaj AVQueen Mary University of LondonQueen Mary University of London (Queen Mary)National Institute for Health Research (NIHR)Wellcome Trust8420https://www.ebi.ac.uk/biostudies/studies/S-EPMC11439042biostudies-literatureUnknown15(1)Postnatal growth failure is often attributed to dysregulated somatotropin action, however marked genetic and phenotypic heterogeneity exist. We report five patients from three families who present with short stature, immune dysfunction, atopic eczema and gastrointestinal pathology associated with recessive variants in QSOX2. QSOX2 encodes a nuclear membrane protein linked to disulphide isomerase and oxidoreductase activity. Loss of QSOX2 disrupts Growth hormone-mediated STAT5B nuclear translocation despite enhanced Growth hormone-induced STAT5B phosphorylation. Moreover, patient-derived dermal fibroblasts demonstrate Growth hormone-induced mitochondriopathy and reduced mitochondrial membrane potential. Located at the nuclear membrane, QSOX2 acts as a gatekeeper for regulating stabilisationNature communicationsQSOX2 Deficiency-induced short stature, gastrointestinal dysmotility and immune dysfunction.PMC11439042NIHR300098MEAG2C4RElfeky RIshida MJoensuu AHwa VAndrews ARybak AMaharaj AVJoshi AMcGuffin LJStorr HLO'Toole EAKantojarvi KElmslie FJia RYPerry JRBfalseQSOX2 Deficiency-induced short stature, gastrointestinal dysmotility and immune dysfunction.Postnatal growth failure is often attributed to dysregulated somatotropin action, however marked genetic and phenotypic heterogeneity exist. We report five patients from three families who present with short stature, immune dysfunction, atopic eczema and gastrointestinal pathology associated with recessive variants in QSOX2. QSOX2 encodes a nuclear membrane protein linked to disulphide isomerase and oxidoreductase activity. Loss of QSOX2 disrupts Growth hormone-mediated STAT5B nuclear translocation despite enhanced Growth hormone-induced STAT5B phosphorylation. Moreover, patient-derived dermal fibroblasts demonstrate Growth hormone-induced mitochondriopathy and reduced mitochondrial membrane potential. Located at the nuclear membrane, QSOX2 acts as a gatekeeper for regulating stabilisation2024-01-01T00:00:00Z2024 Sep2026-06-02T23:03:09.721Z2025-04-04T19:38:26.188ZS-EPMC114390423934181510.1038/s41467-024-52587-w