5
STAT5b deficiency: Lessons from STAT5b gene mutations

https://doi.org/10.1016/j.beem.2010.09.003Get rights and content

Growth hormone (GH) regulates insulin-like growth factor (IGF)-I production primarily through activation of the GH receptor (GHR)-signal transducer and activator of transcription (STAT)-5b signaling cascade. One of four STAT proteins (STAT1, −3, −5a and −5b) activated by the GH–GHR system, the critical importance of STAT5b in IGF-I production became evident with the identification of homozygous, autosomal recessive STAT5b mutations in patients who presented with severe postnatal growth failure, growth hormone insensitivity syndrome (GHIS) and marked IGF-I deficiency. Unlike GHIS due to GHR mutations, patients carrying STAT5b mutations also presented with chronic pulmonary disease and evidence of perturbations of T-cell homeostasis. At present, no single treatment(s) is available to improve both poor statural growth and immune deficiency. Continued clinical evaluations of patients with STAT5b mutations and elucidating the impact of the mutation on STAT5b structure and function, are important to understanding the pathophysiology of this rare, complex, disease (MIM 245590).

Introduction

The cytosolic signal transducers and activators of transcription (STAT) family of proteins are aptly named for their unique abilities to function both as signal transducers and as transcription factors. In humans, the seven STATs (STAT1, −2, −3, −4, −5a, −5b and −6) are expressed in multiple cell types, are activated by many growth factors, including growth hormone (GH), prolactin and cytokines, such as the interleukins (IL), and participate in a diverse set of biological activities.1 The specific STAT proteins that are recruited by ligand-activated signaling systems may depend on the specific tyrosine-based motifs in the receptor components2 and on structural features within the Src homology 2 (SH2) domains of the STAT proteins.3 While the preferential recruitment of one STAT over another is still not fully understood, specificity of activation is clearly critical, and the activation (i.e. tyrosine phosphorylation) processes, themselves, are well documented.

Molecular defects in the STAT1, STAT3 and STAT5b genes have been identified in the past decade. Mutations in the STAT14, 5, 6 (MIM+600555;) and STAT37, 8 (MIM #147060;) genes were first described for immuno-compromised patients, while mutations in the STAT5b gene were first described in patients presenting with growth hormone insensitivity (GHI) syndrome (MIM262500), severe insulin-like growth factor (IGF)-1 deficiency (IGFD) and profound postnatal growth retardation.9 GH promotes normal postnatal growth by regulating the expression of IGF-I, through signaling cascades that include STAT5b signal transduction. The dramatic growth failure of subjects carrying STAT5b mutations, in association with resistance to GH and severe IGFD, emphasizes the importance of the STAT5b signaling pathway for GH-promoted regulation of IGF1 expression. The STAT5b mutations, similar to defective STAT1 and STAT3 genes, also confer unique and distinct immuno-deficiencies, correlating with the ability of cytokines involved in immunity to activate STAT5b.10, 11 In this chapter, the critical role of STAT5b in GH-induced human growth will be summarized.

Section snippets

Gene structure

The human STAT5b protein is encoded by a single STAT5b gene that spans 77.23 kilobases (kb), within a 204.4 kb region that also carries the STAT5a and STAT3 genes, located on chromosome 17q11.2. The STAT5b and STAT5a genes are found in inverted positions, 11 kb apart. Although the STAT5a gene (24.4 kb) is considerably smaller than the STAT5b gene, the two genes share a sequence identity of 93.6% in their exonic, cDNA sequences, supporting an evolutionary concept of gene duplication.12 The STAT5b

The GH–IGF-I axis: STAT5b signaling pathway

The postnatal growth-promoting effects of GH are mediated primarily through regulating expression of IGF-I, both circulating and peripheral, as demonstrated in rodent models17, 18 and in case studies in humans.19, 20, 21, 22, 23 In humans, three reported cases of homozygous IGF1 mutations have supported the importance of IGF-I peptides for both in utero and postnatal growth, as these cases have been characterized by intrauterine growth retardation (IUGR) and severe postnatal growth failure

The Stat5b−/− mouse model for growth

The experimental disruption of each of the seven STAT proteins in rodent models implicated STAT5 and, in particular, STAT5b as critical for postnatal growth. Stat5b−/− mice displayed loss of sexually dimorphic growth, with a concomitant 30–50% reduction of serum IGF-I concentrations.38, 39 While male Stat5b−/− mice were reduced in size to wild-type female mice, no differences were observed between Stat5b−/− and Stat5b+/+ female mice, suggesting a critical role for Stat5b in male/female

Molecular defects in the STAT5b gene

Molecular defects along the GH–IGF-I axis are extremely rare, but recent identification of human STAT5b mutations associated with severe growth failure, marked IGF-I deficiency, and insensitivity to GH, provided the first definitive demonstrations that the STAT5b signaling pathway is critical for GH-induced IGF-I production and normal growth in humans (see Table 1, Table 2, Table 3,41, 42).

The first STAT5b mutation, reported in 2003, was identified in a 16 year old female who was severely

Diagnosis of STAT5b deficiency

As described above, patients with mutations of the STAT5b gene identified to date resemble patients with GHR defects in the following characteristics:

  • 1)

    near-normal prenatal growth;

  • 2)

    profound postnatal growth failure;

  • 3)

    phenotypic features of frontal bossing, midfacial hypoplasia, sparse hair;

  • 4)

    low serum IGF-I, IGFBP-3 and ALS;

  • 5)

    normal-elevated serum GH (basal and/or stimulated);

  • 6)

    normal serum GHBP;

  • 7)

    poor IGF-I and IGFBP-3 response to GH; and

  • 8)

    poor statural response to GH therapy.

Unlike most patients with

Perspective and summary

The identification of patients with unequivocal defects in the GH signaling cascade, specifically, STAT5b signaling, has furthered our understanding of the molecular basis of growth failure associated with primary IGFD. The STAT5b mutations identified to date were autosomal recessive, suggesting that haploinsufficiency of STAT5b has minimal effects on IGF-I expression and on growth. Significantly, in humans, unlike in rodent models, the presence of STAT5a cannot compensate for the loss of

Acknowledgement

We thank Dr Horacio Domené, Dr Mirta Miras, and Dr Merih Berberoglu, and their colleagues, for sharing unpublished information.

References (64)

  • D.J. Chia et al.

    Aberrant folding of a mutant STAT5b causes growth hormone insensitivity and proteasomal dysfunction

    Journal of Biological Chemistry

    (2006)
  • A. Martinez et al.

    Novel STAT5b gene mutation in a patient presenting GH insensitivity and innumodeficiency

    Hormone Research

    (2007)
  • M.A. Burchill et al.

    Interleukin-2 receptor signaling in regulatory T cell development and homeostasis

    Immunology Letters

    (2007)
  • T.R. Torgerson

    Immune dysregulation in primary immunodeficiency disorders

    Immunology and Allergy Clinics of North America

    (2008)
  • E. Zorn et al.

    IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo

    Blood

    (2006)
  • Z. Yao et al.

    Nonredundant roles for STAT5a/b in directly regulating Foxp3

    Blood

    (2007)
  • J.L. Riley et al.

    Human T regulatory cell therapy: take a billion or so and call me in the morning

    Immunity

    (2009)
  • G.M. Bright et al.

    Recombinant human insulin-like growth factor-1 treatment: ready for primetime

    Endocrinology Metabolism Clinics of North America

    (2009)
  • D.E. Levy et al.

    STATs: transcriptional control and biological impact

    Nature Reviews Molecular Cell Biology

    (2002)
  • N. Stahl et al.

    Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors

    Science

    (1995)
  • T. Kaneko et al.

    Loops govern SH2 domain specificity by controlling access to binding pockets

    Science Signalling

    (2010)
  • S. Dupuis et al.

    Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation

    Science

    (2001)
  • S. Dupuis et al.

    Impaired response to interferon-α/β and lethal viral disease in human STAT1 deficiency

    Nature Genetics

    (2003)
  • A. Chapgier et al.

    Human complete STAT-1 deficiency is associated with defective type 1 and II IFN responses in vitro but immunity to some low virulence viruses in vivo

    Journal of Immunology

    (2006)
  • Y. Minegishi et al.

    Dominant-negative mutations in the DNA-binding domains of STAT3 cause hyper-IgE syndrome

    Nature

    (2007)
  • E.D. Renner et al.

    STAT3 mutation in the original patient with Job's syndrome

    New England Journal of Medicine

    (2007)
  • E.M. Kofoed et al.

    Growth-hormone insensitivity (GHI) associated with a STAT-5b mutation

    New England Journal of Medicine

    (2003)
  • W.J. Leonard et al.

    JAKS and STATS: biological implications

    Annual Review of Immunology

    (1998)
  • L. Hennighausen et al.

    Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B

    Genes & Development

    (2008)
  • S.A. Beausoleil et al.

    A probability-based approach for high-throughput protein phosphorylation analysis and site localization

    Nature Biotechnology

    (2006)
  • V. Mayya et al.

    Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions

    Science Signalling

    (2009)
  • C. Choudhary et al.

    Lysine acetylation targets protein complexes and co-regulates major cellular functions

    Science

    (2009)

    • Cited by (95)

    • Type 1 diabetes and inborn errors of immunity: Complete strangers or 2 sides of the same coin?

      2023, Journal of Allergy and Clinical Immunology

    • Atypical STAT5B deficiency, severe short stature and mild immunodeficiency associated with a novel homozygous STAT5B Variant

      2023, Molecular and Cellular Endocrinology

    • Above the Regular Tide: Primary Immune Regulatory Disorders (PIRD) Diagnosis and Treatment Considerations

      2022, Encyclopedia of Infection and Immunity

    • Disorders of growth

      2021, Biochemical and Molecular Basis of Pediatric Disease

    • Human growth disorders associated with impaired GH action: Defects in STAT5B and JAK2

      2021, Molecular and Cellular Endocrinology

    • Activating mutations of STAT3: Impact on human growth

      2020, Molecular and Cellular Endocrinology
      Citation Excerpt :

      However, a dysregulation of the GH-IGFI axis may also be involved, since STAT5B is a major transducer of the GH signaling pathway and SOCS3 inhibits JAK2 phosphorylation via binding to membrane-proximal GH receptor tyrosines 333 and 338 (Ram and Waxman, 1999) (Fig. 2). In addition, some clinical features presented in STAT3 GOF patients are also common in patients with STAT5B LOF mutations (Hwa et al., 2011; Hwa, 2016), suggesting that decreased STAT5B activity may explain, at least in part, the phenotype. Inactivating mutations in STAT5B lead to short stature associated with immune dysregulation, interstitial lung disease, eczema, recurrent skin and respiratory infections, and several autoimmune manifestations (Hwa et al., 2011; Hwa, 2016).

    View all citing articles on Scopus
    d

    Tel: +1 650 867 4592; Fax: +1 650 498 5560.

    e

    Tel: +31 71 5150430; Fax: +31 71 5248198.

    f

    Tel: +1 650 207 4519; Fax: +1 504 494 0428.

    View full text
    Copyright © 2010 Elsevier Ltd. All rights reserved.