CoChat
Sign Up
Cited by 9Growth Hormone and Insulin-like Growth FactorsImmunodeficiency and Autoimmune DisordersGenomics and Rare Diseases

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

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

Open access
Maharaj, Avinaash V., Ishida, Miho, Rybak, Anna, Elfeky, Reem, Andrews, Afiya, Joshi, Aakash, Elmslie, Frances, Joensuu, Anni, Kantojärvi, Katri, Jia, Raina Y., Perry, John R. B., O’Toole, Edel A., McGuffin, Liam J., Hwa, Vivian, Storr, Helen L.·2024·Nature Communications
DOI 10.1038/s41467-024-52587-wPMC PMC11439042

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

Abstract Postnatal growth failure is often attributed to dysregulated somatotropin action, however marked genetic and phenotypic heterogeneity exist. We report four patients from two families who present with short stature, immune dysfunction, atopic eczema and gut-associated pathology associated with recessive variants in QSOX2. QSOX2 encodes a nuclear membrane protein linked to disulphide isomerase and oxidoreductase activity. Loss of QSOX2 disrupts GH-mediated STAT5B nuclear translocation despite enhanced GH-induced STAT5B phosphorylation. Moreover, patient-derived dermal fibroblasts demonstrate novel GH-induced mitochondriopathy and reduced mitochondrial membrane potential. We describe a definitive role of QSOX2 in modulating human growth likely due to impairment of STAT5B downstream activity and mitochondrial dynamics leading to growth failure, immune dysregulation and gut dysfunction. Located at the nuclear membrane, QSOX2 acts as a gatekeeper for regulating stabilisation and import of p-STAT5B. Furthermore, our work suggests that therapeutic recombinant IGF-1 may circumvent the GH-mediated STAT5B molecular defect and potentially alleviate organ specific disease.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-024-52587-w

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 67

  1. Murray, P. G., Clayton, P. E. & Chernausek, S. D. A genetic approach to evaluation of short stature of undetermined cause. Lancet Diabetes Endocrinol. 6, 564–574 (2018). · DOI
  2. Sovio, U. et al. Genetic determinants of height growth assessed longitudinally from infancy to adulthood in the Northern Finland Birth Cohort 1966. PLoS Genet. 5, e1000409 (2009). · DOI
  3. Storr, H. L. et al. Nonclassical GH insensitivity: Characterization of mild abnormalities of GH action. Endocr. Rev. 40, 476–505 (2019). · DOI
  4. Klammt, J. et al. Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation. Nat. Commun. 9, 2105 (2018). · DOI
  5. Vidarsdottir, S. et al. Clinical and biochemical characteristics of a male patient with a novel homozygous STAT5b mutation. J. Clin. Endocrinol. Metab. 91, 3482–3485 (2006). · DOI
  6. Bezrodnik, L. et al. Long-term follow-up of STAT5B deficiency in three Argentinian patients: Clinical and immunological Ffeatures. J. Clin. Immunol. 35, 264–272 (2015). · DOI
  7. Hwa, V. Human growth disorders associated with impaired GH action: Defects in STAT5B and JAK2. Mol. Cell Endocrinol. 519, 111063 (2021). · DOI
  8. Krone, K. A. et al. Signal transducer and activator of transcription 5B deficiency–associated lung disease. Am. J. Respir. Crit. Care Med. 205, 1245–1250 (2022). · DOI
  9. Smith, M. R., Satter, L. R. F. & Vargas-Hernández, A. STAT5b: A master regulator of key biological pathways. Front Immunol. 13, 1025373 (2023). · DOI
  10. Wittke, I. et al. Neuroblastoma-derived sulfhydryl oxidase, a new member of the sulfhydryl oxidase/quiescin6 family, regulates sensitization to interferon γ-induced cell death in human neuroblastoma cells. Cancer Res. 63, 7742–7752 (2003).
  11. Morel, C. et al. Involvement of sulfhydryl oxidase QSOX1 in the protection of cells against oxidative stress-induced apoptosis. Exp. Cell Res. 313, 3971–3982 (2007). · DOI
  12. Li, Y. et al. QSOX2 is an E2F1 target gene and a novel serum biomarker for monitoring tumor growth and predicting survival in advanced NSCLC. Front. Cell Dev. Biol. 9, 688798 (2021). · DOI
  13. Okada, Y. et al. A genome-wide association study in 19 633 Japanese subjects identified LHX3-QSOX2 and IGF1 as adult height loci. Hum. Mol. Genet. 19, 2303–2312 (2010). · DOI
  14. Yengo, L. et al. A saturated map of common genetic variants associated with human height. Nature 610, 704–712 (2022). · DOI · Paper page
  15. Carlsson, L. M. S. Partial growth hormone insensitivity in childhood. Baillière’s Clin. Endocrinol. Metab. 10, 389–400 (1996). · DOI
  16. Attie, K. M., Carlsson, L. M. S. & Rundle, A. C. Evidence for partial growth hormone (gh) insensitivity among “Idiopathic” short stature (iss) patients treated with growth hormone. Pediatr. Res. 33, S48–S48 (1993). · DOI
  17. Kofoed, E. M. et al. Growth hormone insensitivity associated with a STAT5b mutation. N. Engl. J. Med. 349, 1139–1147 (2003). · DOI
  18. Vairamani, K. et al. Novel dominant-negative GH receptor mutations expands the spectrum of GHI and IGF-I deficiency. J. Endocr. Soc. 1, 345–358 (2017). · DOI
  19. Steinhaus, R. et al. Mutationtaster2021. Nucleic Acids Res. 49, W446–W451 (2021). · DOI
  20. GTEx Consortium. The GTEx consortium atlas of genetic regulatory effects across human tissues. Science 369, 1318–1330 (2020). · DOI · Paper page
  21. Ghoussaini, M. et al. Open targets genetics: systematic identification of trait-associated genes using large-scale genetics and functional genomics. Nucleic Acids Res. 49, D1311–D1320 (2021). · DOI
  22. Desmet, F.-O. et al. Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37, e67 (2009). · DOI
  23. Shamsani, J. et al. A plugin for the Ensembl Variant Effect Predictor that uses MaxEntScan to predict variant spliceogenicity. Bioinformatics 35, 2315–2317 (2019). · DOI
  24. Chueh, F.-Y., Leong, K.-F. & Yu, C.-L. Mitochondrial translocation of signal transducer and activator of transcription 5 (STAT5) in leukemic T cells and cytokine-stimulated cells. Biochem. Biophys. Res. Commun. 402, 778–783 (2010). · DOI
  25. Chueh, F.-Y., Chang, Y.-L., Wu, S.-Y. & Yu, C.-L. Signal transducer and activator of transcription 5a (STAT5a) represses mitochondrial gene expression through direct binding to mitochondrial DNA. Biochem. Biophys. Res. Commun. 527, 974–978 (2020). · DOI
  26. Tresse, E. et al. IFN-β rescues neurodegeneration by regulating mitochondrial fission via STAT5, PGAM5, and Drp1. EMBO J. 40, e106868 (2021). · DOI
  27. He, M. et al. Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci. Hum. Mol. Genet. 24, 1791–1800 (2015). · DOI · Paper page
  28. Lango Allen, H. et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010). · DOI · Paper page
  29. Han, S. et al. Identification of exon skipping events associated with Alzheimer’s disease in the human hippocampus. BMC Med. Genom. 12, 13 (2019). · DOI
  30. Kingdom, R. & Wright, C. F. Incomplete penetrance and variable expressivity: From clinical studies to population cohorts. Front. Genet. 13, 920390 (2022). · DOI
  31. Russo, M. et al. Variable phenotypes are associated with PMP22 missense mutations. Neuromuscul. Disord. 21, 106–114 (2011). · DOI
  32. Shen, N. et al. Co-expression of phenylalanine hydroxylase variants and effects of interallelic complementation on in vitro enzyme activity and genotype-phenotype correlation. Mol. Genet. Metab. 117, 328–335 (2016). · DOI
  33. Saeed, S. et al. Loss-of-function mutations in ADCY3 cause monogenic severe obesity. Nat. Genet. 50, 175–179 (2018). · DOI
  34. Pugliese-Pires, P. N. et al. A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings. Eur. J. Endocrinol. 163, 349–355 (2010). · DOI
  35. Vargas-Hernández, A. et al. Human STAT5b mutation causes dysregulated human natural killer cell maturation and impaired lytic function. J. Allergy Clin. Immunol. 145, 345–357 (2020). · DOI
  36. Cohen, A. C. et al. Cutting edge: Decreased accumulation and regulatory function of CD4+CD25high T cells in human STAT5b deficiency1. J. Immunol. 177, 2770–2774 (2006). · DOI
  37. Caldirola, M. S., Rodríguez Broggi, M. G., Gaillard, M. I., Bezrodnik, L. & Zwirner, N. W. Primary immunodeficiencies unravel the role of IL-2/CD25/STAT5b in human natural killer cell maturation. Front. Immunol. 9, 1429 (2018). · DOI
  38. Pelham, S. J. et al. STAT5B restrains human B-cell differentiation to maintain humoral immune homeostasis. J. Allergy Clin. Immunol. 150, 931–946 (2022). · DOI
  39. Walenkamp, M. J. E. et al. Growth hormone secretion and immunological function of a male patient with a homozygous STAT5b mutation. Eur. J. Endocrinol. 156, 155–165 (2007). · DOI
  40. Catli, G. et al. Atypical STAT5B deficiency, severe short stature and mild immunodeficiency associated with a novel homozygous STAT5B Variant. Mol. Cell. Endocrinol. 559, 111799 (2023). · DOI
  41. Paldino, G. et al. Analysis of a series of Italian APECED patients with autoimmune hepatitis and gastro-enteropathies. Front. Immunol. 14, 1172369 (2023). · DOI
  42. Tanno, A. et al. Decreased expression of a phagocytic receptor Siglec-1 on alveolar macrophages in chronic obstructive pulmonary disease. Respir. Res. 21, 30 (2020). · DOI
  43. Villamayor, L. et al. The IFN-stimulated gene IFI27 counteracts innate immune responses after viral infections by interfering with RIG-I signaling. Front. Microbiol. 14, 1176177 (2023). · DOI
  44. Lee, J. E. et al. Nongenomic STAT5-dependent effects on Golgi apparatus and endoplasmic reticulum structure and function. Am. J. Physiol.-Cell Physiol. 302, C804–C820 (2012). · DOI
  45. Zhang, L. et al. Mitochondrial STAT5A promotes metabolic remodeling and the Warburg effect by inactivating the pyruvate dehydrogenase complex. Cell Death Dis. 12, 1–12 (2021). · DOI · Paper page
  46. Finsterer, J. & Frank, M. Gastrointestinal manifestations of mitochondrial disorders: a systematic review. Ther. Adv. Gastroenterol. 10, 142–154 (2017). · DOI
  47. Dubé, P. E., Forse, C. L., Bahrami, J. & Brubaker, P. L. The essential role of insulin-like growth factor-1 in the intestinal tropic effects of glucagon-like peptide-2 in mice. Gastroenterology 131, 589–605 (2006). · DOI
  48. Chernausek, S. D. et al. Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity. J. Clin. Endocrinol. Metab. 92, 902–910 (2007). · DOI
  49. Rodrigues, C. H., Pires, D. E. & Ascher, D. B. DynaMut: predicting the impact of mutations on protein conformation, flexibility and stability. Nucleic Acids Res. 46, W350–W355 (2018). · DOI · Paper page
  50. Capriotti, E., Fariselli, P. & Casadio, R. I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Res. 33, W306–W310 (2005). · DOI
  51. Worth, C. L., Preissner, R. & Blundell, T. L. SDM—a server for predicting effects of mutations on protein stability and malfunction. Nucleic Acids Res. 39, W215–W222 (2011). · DOI
  52. Pires, D. E. V., Ascher, D. B. & Blundell, T. L. DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach. Nucleic Acids Res. 42, W314–W319 (2014). · DOI · Paper page
  53. Cheng, J., Randall, A. & Baldi, P. Prediction of protein stability changes for single-site mutations using support vector machines. Proteins Struct. Funct. Bioinform. 62, 1125–1132 (2006). · DOI
  54. Pires, D. E. V., Ascher, D. B. & Blundell, T. L. mCSM: predicting the effects of mutations in proteins using graph-based signatures. Bioinformatics 30, 335–342 (2014). · DOI · Paper page
  55. McGuffin, L. J. et al. Prediction of protein structures, functions and interactions using the IntFOLD7, MultiFOLD and ModFOLDdock servers. Nucleic Acids Res. 51, W274–W280 (2023). · DOI
  56. Tomkins, J. E. et al. PINOT: an intuitive resource for integrating protein-protein interactions. Cell Commun. Signal. 18, 92 (2020). · DOI
  57. Jones, D. T. & Cozzetto, D. DISOPRED3: precise disordered region predictions with annotated protein-binding activity. Bioinformatics 31, 857–863 (2015). · DOI
  58. Nugent, T. & Jones, D. T. Transmembrane protein topology prediction using support vector machines. BMC Bioinform. 10, 159 (2009). · DOI
  59. Gardner, E. J. et al. Damaging missense variants in IGF1R implicate a role for IGF-1 resistance in the etiology of type 2 diabetes. Cell Genom. 2, None (2022).
  60. McLaren, W. et al. The ensembl variant effect predictor. Genome Biol. 17, 122 (2016). · DOI · Paper page
  61. Loh, P.-R. et al. Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat. Genet. 47, 284–290 (2015). · DOI · Paper page
  62. Saari, A. et al. New Finnish growth references for children and adolescents aged 0 to 20 years: Length/height-for-age, weight-for-length/height, and body mass index-for-age. Ann. Med. 43, 235–248 (2011). · DOI
  63. Maharaj, A. et al. Predicted benign and synonymous variants in CYP11A1 cause primary adrenal insufficiency through missplicing. J. Endocr. Soc. 3, 201–221 (2019). · DOI
  64. Guesdon, F. et al. Expression of a glycosylphosphatidylinositol-anchored ligand, growth hormone, blocks receptor signalling. Biosci. Rep. 32, 653–660 (2012). · DOI
  65. Ran, F. A. et al. Genome engineering using the CRISPR-Cas9 system. Nat. Protoc. 8, 2281–2308 (2013). · DOI · Paper page
  66. Kelly, A., Tang, R., Becker, S. & Stanley, C. A. Poor specificity of low growth hormone and cortisol levels during fasting hypoglycemia for the diagnoses of growth hormone deficiency and adrenal insufficiency. Pediatrics 122, e522–e528 (2008). · DOI
  67. Chesover, A. D. & Dattani, M. T. Evaluation of growth hormone stimulation testing in children. Clin. Endocrinol. 84, 708–714 (2016). · DOI

Metadata

Authors
Maharaj, A. V., Ishida, M., Rybak, A., Elfeky, R., Andrews, A., Joshi, A., Elmslie, F., Joensuu, A., Kantojärvi, K., Jia, R. Y., Perry, J. R. B., O’Toole, E. A., McGuffin, L. J., Hwa, V., & Storr, H. L.
Affiliations
  • Queen Mary University of London (GB)
  • Great Ormond Street Hospital (GB)
  • St George’s University Hospitals NHS Foundation Trust (GB)
  • Finnish Institute for Health and Welfare (FI)
  • University of Cambridge (GB)
  • University of Reading (GB)
  • Cincinnati Children's Hospital Medical Center (US)
Corresponding author
  • Maharaj, Avinaash V.
  • Hwa, Vivian
  • Storr, Helen L.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-09-28
Volume
15
Issue
1
Pages
8420-8420
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-52587-w
PMC
PMC11439042
OpenAlex
W4402940367
Cited by
9
References
1
Citations by year
2026: 4 · 2025: 5
FWCI
2.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • CentAUR (University of Reading) (submittedVersion, cc-by-nc-nd)
  • St George's Online Research Archive (St George's University of London) (submittedVersion, cc-by-nc-nd)
  • Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
Funders
  • DH | National Institute for Health Research (NIHR300098)
  • Queen Mary University of London (MEAG2C4R)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
short stature, growth hormone insensitivity, STAT5B, growth hormone signaling, mitochondrial dysfunction, mitochondrial membrane potential, nuclear membrane proteins, immune dysfunction, atopic dermatitis, gastrointestinal motility disorders, recessive mutations, postnatal growth failure
MeSH terms
Child, Child, Preschool, Dermatitis, Atopic, Female, Fibroblasts, Gastrointestinal Diseases, Growth Disorders, Humans, Immune System Diseases, Insulin-Like Growth Factor I, Male, Mitochondria, Pedigree, Phosphorylation, Growth Hormone, Human Growth Hormone, STAT5 Transcription Factor, Oxidoreductases Acting on Sulfur Group Donors, Membrane Potential, Mitochondrial

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review