Best Practice & Research Clinical Endocrinology & Metabolism
5STAT5b deficiency: Lessons from STAT5b gene mutations
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.
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2020, Molecular and Cellular EndocrinologyCitation 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).
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