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Endocrine Abstracts (2022) 85 OC1.1 | DOI: 10.1530/endoabs.85.OC1.1

BSPED2022 Oral Communications Oral Communications 1 (2 abstracts)

Defects in QSOX2, a novel regulator of STAT5B nuclear import and transcriptional activity, lead to severe post-natal growth restriction

Avinaash Maharaj 1 , Afiya Andrews 1 , Sumana Chatterjee 1 , Vivian Hwa 2 & Helen Storr 1


1William Harvey Research Institute, London, United Kingdom; 2Cincinnati Center for Growth Disorders, Cincinnati, USA


Background: Growth Hormone Insensitivity (GHI) is characterised by short stature and functional IGF-I deficiency associated with normal/elevated GH levels. Marked genetic and phenotypic heterogeneity exist, and heritable defects in GH-IGF-I axis associated pathways account for mild-moderate to severe GHI. We report non-consanguineous twin brothers who present with short stature and bi-allelic mutations in QSOX2 encoding a nuclear membrane protein. Genome-wide association studies have identified the LHX3-QSOX2 locus as a significant height quantitative trait locus. We hypothesise QSOX2 is a novel regulator of STAT5B nuclear translocation.

Methods: Variant constructs generated by mutagenesis of an N-terminal FLAG tagged-QSOX2 cDNA were expressed in HEK293-hGHR cells. QSOX2 and STAT5B cellular localisation were assessed by immunoblotting/immunofluorescence. Nano-luciferase complementation and dual luciferase reporter assays evaluated QSOX2-STAT5B interactions and GH-induced transcriptional activity, respectively. Mitochondrial morphology and membrane potential of patient fibroblasts were examined by confocal microscopy and TMRE assays.

Results: Monozygotic twin brothers presented with severe growth restriction, immunodeficiency, relative macrocephaly, mild dysmorphism, recurrent infections, oral feeding aversion and gastroparesis. Blood profiling revealed low IgM levels and elevated basal levels of phosphorylated STAT5 compared to controls. Next generation sequencing revealed compound heterozygous variants in QSOX2; a novel paternally inherited single base deletion, predicted to result in a frameshift truncation and a maternally inherited missense variant, predicted deleterious in silico. We demonstrated a direct interaction between QSOX2 and STAT5B. Nano-luciferase complementation assays revealed attenuation of the interaction of both mutants with STAT5B when compared to wild type. Both mutations led to robust tyrosine phosphorylation of STAT5 following GH agonist stimulation with concomitant cytosolic accumulation and attenuation of nuclear translocation of STAT5B. This effect was phenocopied in patient-derived dermal fibroblasts and similar to the STAT5B p.Gln177Pro mutant which disrupts the CCD, suggesting that this domain is integral for interaction with QSOX2. Both mutants exhibited reduced STAT5B downstream transcriptional activity. A distinct mitochondrial phenotype was also observed in patient fibroblasts.

Conclusion: We describe a definitive role of QSOX2 in modulating human growth, broadening the GHI spectrum. Deficiency of QSOX2 impairs STAT5B downstream activity and mitochondrial dynamics leading to a unique syndrome of postnatal growth failure and mild immunodeficiency.

Volume 85

49th Annual Meeting of the British Society for Paediatric Endocrinology and Diabetes

Belfast, Ireland
02 Nov 2022 - 04 Nov 2022

British Society for Paediatric Endocrinology and Diabetes 

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