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

Avinaash V. Maharaj (), Miho Ishida, Anna Rybak, Reem Elfeky, Afiya Andrews, Aakash Joshi, Frances Elmslie, Anni Joensuu, Katri Kantojärvi, Raina Y. Jia, John R. B. Perry, Edel A. O’Toole, Liam J. McGuffin, Vivian Hwa () and Helen L. Storr ()
Additional contact information
Avinaash V. Maharaj: Charterhouse Square
Miho Ishida: Charterhouse Square
Anna Rybak: Great Ormond Street Hospital
Reem Elfeky: Great Ormond Street Hospital
Afiya Andrews: Charterhouse Square
Aakash Joshi: St George’s University Hospitals NHS Foundation Trust
Frances Elmslie: St George’s University Hospitals NHS Foundation Trust
Anni Joensuu: Finnish Institute for Health and Welfare
Katri Kantojärvi: Finnish Institute for Health and Welfare
Raina Y. Jia: School of Clinical Medicine
John R. B. Perry: School of Clinical Medicine
Edel A. O’Toole: Queen Mary University of London
Liam J. McGuffin: University of Reading
Vivian Hwa: University of Cincinnati College of Medicine
Helen L. Storr: Charterhouse Square

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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 stabilisation and import of phosphorylated-STAT5B. Altogether, QSOX2 deficiency modulates human growth by impairing Growth hormone-STAT5B downstream activities and mitochondrial dynamics, which contribute to multi-system dysfunction. Furthermore, our work suggests that therapeutic recombinant insulin-like growth factor-1 may circumvent the Growth hormone-STAT5B dysregulation induced by pathological QSOX2 variants and potentially alleviate organ specific disease.

Date: 2024
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DOI: 10.1038/s41467-024-52587-w

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