Journal Article

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

Ishida, Miho, Joensuu, Anni, Storr, Helen L., Hwa, Vivian, Andrews, Afiya, Jia, Raina Y., Maharaj, Avinaash V., Elfeky, Reem, O’Toole, Edel A., McGuffin, Liam J., Rybak, Anna, Joshi, Aakash, Perry, John R. B., Elmslie, Frances, Kantojärvi, Katri

2024

Overview

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. Defects in growth hormone (GH) action account for a substantial percentage of endocrine causes of growth failure. Here, the authors report that QSOX2 deficiency modulates human growth by impairing GH-STAT5B downstream activities and mitochondrial dynamics, contributing to multi-system dysfunction.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14 / 14/19 / 38 / 38/1 / 38/109 / 38/22 / 38/23 / 38/77 / 38/88 / 38/90 / 631/208/457/649/2219 / 631/80/304 / 692/163/2743/1530 / 82/80 / 96 / 96/106 / Atopy / Child / Child, Preschool / Dermatitis, Atopic - genetics / Dermatitis, Atopic - immunology / Dermatitis, Atopic - pathology / Eczema / Female / Fibroblasts - metabolism / Gastrointestinal Diseases - genetics / Gastrointestinal Diseases - pathology / Growth Disorders - genetics / Growth Disorders - pathology / Growth factors / Growth Hormone - deficiency / Growth Hormone - metabolism / Growth hormones / Heterogeneity / Human Growth Hormone - deficiency / Human Growth Hormone - genetics / Human Growth Hormone - metabolism / Humanities and Social Sciences / Humans / Immune System Diseases - genetics / Immune System Diseases - pathology / Insulin-like growth factor I / Insulin-Like Growth Factor I - genetics / Insulin-Like Growth Factor I - metabolism / Male / Membrane potential / Membrane Potential, Mitochondrial / Membranes / Mitochondria / Mitochondria - metabolism / multidisciplinary / Nuclear transport / Oxidoreductase / Oxidoreductases Acting on Sulfur Group Donors - deficiency / Oxidoreductases Acting on Sulfur Group Donors - genetics / Pedigree / Phosphorylation / Science / Science (multidisciplinary) / Skin diseases / STAT5 Transcription Factor - genetics / STAT5 Transcription Factor - metabolism / Translocation