Severe Growth Hormone Insensitivity Resulting from Total Absence of Signal Transducer and Activator of Transcription 5b

Hwa, Vivian; Little, Brian M.; Adıyaman, Pelin; Kofoed, Eric M.; Pratt, Katherine L.; Öçal, Gönül; Berberoğlu, Merih; Rosenfeld, Ron G.

doi:10.1210/jc.2005-0515

Cited by 134 publications

(90 citation statements)

References 20 publications

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“…A targeted knockout of Stat5b in mice results in diminished post-natal growth (11,12), and biochemical studies have established that GH requires Stat5b to mediate hormone-induced IGF-I gene transcription (10). Two humans with profound growth deficiency who harbor homozygous Stat5b mutations have been identified (20,34). One individual has a single nucleotide insertion in exon 10 of the Stat5b gene that results in a frameshift mutation and undetectable protein expression (34).…”

Section: Discussionmentioning

confidence: 99%

“…Two humans with profound growth deficiency who harbor homozygous Stat5b mutations have been identified (20,34). One individual has a single nucleotide insertion in exon 10 of the Stat5b gene that results in a frameshift mutation and undetectable protein expression (34). The other has a mis-sense mutation that changes alanine 630 to proline within the SH2 domain of the protein (20).…”

Section: Discussionmentioning

confidence: 99%

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Aberrant Folding of a Mutant Stat5b Causes Growth Hormone Insensitivity and Proteasomal Dysfunction

Chia

Subbian

Buck

et al. 2006

Journal of Biological Chemistry

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A predicted alanine to proline substitution in Stat5b that results in profound short stature, growth hormone insensitivity, and immunodeficiency represents the first natural mutation of this transcription factor in a human. To understand the mechanisms responsible for these pathophysiological abnormalities, we have studied the biochemical and biophysical properties of the mutant Stat5b molecule. In a cellular reconstitution model growth hormone robustly stimulated tyrosine phosphorylation and transcriptional activity of wild-type Stat5b while Stat5b A630P was minimally modified and did not promote reporter gene expression. Steady state levels of Stat5bWT were ϳ3-fold higher than Stat5b A630P in cell extracts prepared with nonionic detergents. Although initial rates of biosynthesis of both proteins were similar, pulse-chase experiments established that the apparent half-life of newly synthesized soluble Stat5b A630P was <15% of Stat5b WT (3.5 h versus >24 h). Stat5bA630P accumulated in cells primarily in cytoplasmic inclusion bodies. Structural analysis of the isolated SH2 domain containing the A630P mutation showed that it resembled the wild-type SH2 segment but that it exhibited reduced thermodynamic stability and slower folding kinetics, displayed an increased hydrophobic surface, and was prone to aggregation in solution. Our results are compatible with a model in which Stat5b A630P is an inactive transcription factor by virtue of its aberrant folding and diminished solubility triggered by a misfolded SH2 domain. The potential for aggregation and formation of cytoplasmic inclusions raises the possibility that Stat5b A630P could produce additional defects through inhibition of proteasome function.Sequence-specific transcription factors are modular proteins containing distinct domains that mediate their actions, including the ability to move among different subcellular compartments, to bind to DNA in chromatin in the nucleus, and to interact with transcriptional co-activators, co-repressors, and other regulatory molecules (1). The Stat 2 family consists of seven related proteins (Stats 1, 2, 3, 4, 5a, 5b, and 6) that are responsible for many of the transcriptional effects of cytokines, growth factors, and hormones (2, 3). Stat proteins are found in latent form in the cytoplasm of unstimulated cells. They are activated upon ligand binding to its receptor by a series of steps consisting of receptorinitiated tyrosine phosphorylation, dimerization, transport into the nucleus, binding to DNA response elements on target genes, and recruitment of a complex of co-activator proteins that stimulate transcription (2, 3).Growth hormone (GH) plays a central role in regulating somatic growth and intermediary metabolism in many vertebrate species, including humans (4). Upon binding to its transmembrane receptor, GH triggers the activation of the receptor-associated tyrosine-protein kinase Jak2, which in addition to recruiting a variety of other signaling molecules leads to the activation of Stats 1, 3, 5a, and 5b (4, 5). Many ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Aberrant Folding of a Mutant Stat5b Causes Growth Hormone Insensitivity and Proteasomal Dysfunction

Chia

Subbian

Buck

et al. 2006

Journal of Biological Chemistry

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“…In the absence of ALS, IGFBP-3 is cleared very quickly, resulting in extremely low serum concentrations (33,77). The transcription of IGFBP-3 is induced by activation of the GH signal transduction pathway, including STAT5b.…”

Section: Regulation Of Gh Secretionmentioning

confidence: 99%

“…Therefore, IGFBP-3 is a valuable biochemical parameter in differentiating a GH receptor or postreceptor defect from an IGF-I or IGF1R defect. In the latter, IGFBP-3 levels are normal (13,14,22), while in patients with a GHR defect or a STAT5b mutation, IGFBP-3 is low (51,52,54,77).…”

Section: Regulation Of Gh Secretionmentioning

confidence: 99%

Genetic disorders in the GH–IGF-I axis in mouse and man

Walenkamp

Wit²

2007

eur j endocrinol

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Animal knockout experiments have offered the opportunity to study genes that play a role in growth and development. In the last few years, reports of patients with genetic defects in GH-IGF-I axis have greatly increased our knowledge of genetically determined causes of short stature. We will present the animal data and human reports of genetic disorders in the GH-IGF-I axis in order to describe the role of the GH-IGF-I axis in intrauterine and postnatal growth. In addition, the effects of the GH-IGF-I axis on the development and function of different organ systems such as brain, inner ear, eye, skeleton, glucose homeostasis, gonadal function, and immune system will be discussed. The number of patients with genetic defects in the GH-IGF-I axis is small, and a systematic diagnostic approach and selective genetic analysis in a patient with short stature are essential to identify more patients. Finally, the implications of a genetic defect in the GH-IGF-I axis for the patient and the therapeutic options will be discussed.European Journal of Endocrinology 157 S15-S26

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“…Rarely, GHI may also result from mutations in signal transducer and activator of transcription 5B gene (STAT5b; OMIM: 604260), the main component of the GH signaling pathway (5). STAT5b also plays an important role in signaling within immune cells, thus clinical immunodefi ciency is common in patients with STAT5b defi ciency, although is not an obligatory phenomenon (4,45,46).…”

Section: Discussionmentioning

confidence: 99%

Novel nonsense mutation (p.Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome

Diniz

Jorge

Arnhold

et al. 2008

Arq Bras Endocrinol Metab

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Background: To date, about sixty different mutations within GH receptor (GHR) gene have been described in patients with GH insensitivity syndrome (GHI). In this report, we described a novel nonsense mutation of GHR. Methods: The patient was evaluated at the age of 6 yr, for short stature associated to clinical phenotype of GHI. GH, IGF-1, and GHBP levels were determined. The PCR products from exons 2-10 were sequenced. Results: The patient had high GH (26 µg/L), low IGF-1 (22.5 ng/ml) and undetectable GHBP levels. The sequencing of GHR exon 5 disclosed adenine duplication at nucleotide 338 of GHR coding sequence (c.338dupA) in homozygous state. Conclusion: We described a novel mutation that causes a truncated GHR and a loss of receptor function due to the lack of amino acids comprising the transmembrane and intracellular regions of GHR protein, leading to GHI.

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Severe Growth Hormone Insensitivity Resulting from Total Absence of Signal Transducer and Activator of Transcription 5b

Abstract: The identification of a second case of severe growth failure associated with STAT5b mutation implicates a unique and critical role for STAT5b in GH stimulation of IGF-I gene expression and statural growth.

Cited by 134 publications

References 20 publications

Aberrant Folding of a Mutant Stat5b Causes Growth Hormone Insensitivity and Proteasomal Dysfunction

Aberrant Folding of a Mutant Stat5b Causes Growth Hormone Insensitivity and Proteasomal Dysfunction

Genetic disorders in the GH–IGF-I axis in mouse and man

Novel nonsense mutation (p.Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome

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