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

Area of Science:

• Genetics and Molecular Biology
• Endocrinology
• Cell Biology

Background:

• Postnatal growth failure is complex, with somatotropin (Growth Hormone) action dysregulation being a key factor.
• Significant genetic and phenotypic variability complicates understanding and treatment of growth disorders.
• The role of specific genes, like QSOX2, in mediating Growth Hormone effects remains incompletely understood.

Purpose of the Study:

• To investigate the genetic basis and molecular mechanisms underlying a specific form of postnatal growth failure.
• To elucidate the function of QSOX2 in Growth Hormone signaling and cellular processes.
• To explore potential therapeutic strategies for patients with QSOX2 deficiency.

Main Methods:

• Genetic analysis of patients from three families with short stature and immune dysfunction.
• Functional studies using patient-derived dermal fibroblasts.
• Assessment of Growth Hormone-mediated STAT5B signaling, nuclear translocation, and phosphorylation.
• Evaluation of mitochondrial function, including membrane potential and mitochondriopathy.

Main Results:

• Identified recessive variants in QSOX2 in five patients presenting with short stature, immune dysfunction, eczema, and gastrointestinal issues.
• Demonstrated that loss of QSOX2 impairs Growth Hormone-mediated STAT5B nuclear translocation despite increased STAT5B phosphorylation.
• Observed Growth Hormone-induced mitochondriopathy and reduced mitochondrial membrane potential in patient fibroblasts.
• Established QSOX2's role as a nuclear membrane gatekeeper for phosphorylated-STAT5B stabilization and import.

Conclusions:

• QSOX2 deficiency impairs Growth Hormone-STAT5B downstream signaling and mitochondrial dynamics, leading to multi-system dysfunction and postnatal growth failure.
• QSOX2 acts as a crucial regulator at the nuclear membrane for Growth Hormone signaling.
• Therapeutic recombinant insulin-like growth factor-1 may bypass QSOX2-related Growth Hormone-STAT5B dysregulation, offering a potential treatment avenue for affected individuals.