QSOX2 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 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.
Authors
- Afiya Andrews (ORCID: https://orcid.org/0000-0003-2390-657X)
- Vivian Hwa
- Anni Joensuu (ORCID: https://orcid.org/0000-0002-7547-7458)
- Miho Ishida (ORCID: https://orcid.org/0000-0002-4769-2273)
- John R. B. Perry (ORCID: https://orcid.org/0000-0001-6483-3771)
- Frances Elmslie
- Katri Kantojärvi (ORCID: https://orcid.org/0000-0002-1294-0310)
- Anna Rybak (ORCID: https://orcid.org/0000-0002-8233-5490)
- Helen L. Storr (ORCID: https://orcid.org/0000-0002-9963-1931)
- Avinaash Maharaj (ORCID: https://orcid.org/0000-0001-8051-3866)
- Raina Jia (ORCID: https://orcid.org/0000-0003-2234-8238)
- Liam James McGuffin (ORCID: https://orcid.org/0000-0003-4501-4767)
- Edel A. O’Toole (ORCID: https://orcid.org/0000-0002-4084-4836)
- Aakash Joshi
- Reem Elfeky (ORCID: https://orcid.org/0000-0003-0729-4251)
Institutions
- Cincinnati Children's Hospital Medical Center (US)
- Queen Mary University of London (GB)
- University of Cambridge (GB)
- Great Ormond Street Hospital (GB)
- St George’s University Hospitals NHS Foundation Trust (GB)
- Finnish Institute for Health and Welfare (FI)
- MRC Epidemiology Unit (GB)
- University College London (GB)
- University of Reading (GB)
- The University of Osaka (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-28
- DOI
- https://doi.org/10.1038/s41467-024-52587-w
- Citations
- 7
- Primary Topic
- RNA regulation and disease
- Type
- article
- Field-Weighted Citation Impact
- 1.64
Funders
- Queen Mary University of London
- Wellcome Trust
- Barts Charity
- Cancer Research UK
- National Institute for Health and Care Research
- Department of Health and Social Care
- Medical Research Council
- Biotechnology and Biological Sciences Research Council