Clinical and Biochemical Characteristics of a Male Patient with a Novel Homozygous STAT5b Mutation

Vidarsdottir, Solrun; Walenkamp, M.J.E.; Pereira, Alberto M.; Karperien, Marcel; Doorn, Jaap van; Duyvenvoorde, Hermine A. van; White, Stefan J.; Breuning, Martijn H.; Roelfsema, Ferdinand; Kruithof, M. Femke; Dissel, Jaap van; Janssen, Riny; Wit, Jan M.; Romijn, Johannes A.

doi:10.1210/jc.2006-0368

Cited by 93 publications

(74 citation statements)

References 19 publications

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“…Genetically modified animals and microarray analysis have provided new insights into the long-known anti-adiposity actions of GH and highlighted a key role for STAT5 in these actions. This is supported by original findings that STAT5b-deleted male mice become obese in later life (Udy et al, 1997;Teglund et al, 1998) and that STAT5b deletion in a mature human was associated with obesity (Vidarsdottir et al, 2006). The anti-obesity actions of GH are enhanced by the pulsatility of GH secretion evident in males (Takahashi et al, 1999) because pulsatile STAT5 activation, which is, as mentioned above, so important for sexual dimorphism in hepatic gene expression (including IGF-1).…”

Section: Gh and Metabolismsupporting

confidence: 63%

Estrogens in the Control of Growth Hormone Actions in Liver

Fernández-Pérez¹,

Flores‐Morales²

2012

Sex Steroids

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Section: Gh and Metabolismsupporting

confidence: 63%

Estrogens in the Control of Growth Hormone Actions in Liver

Fernández-Pérez¹,

Flores‐Morales²

2012

Sex Steroids

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“…Indeed, the elevated prolactin levels are suppressed upon IGF-I administration, in line with the inhibitory action of IGF-I on hypothalamic GHRH neurons (65). In patients with a STAT5b mutation, prolactin levels are even more elevated (52,54,66). This can be explained by the obligatory role of STAT5b in mediating the negative feedback action of prolactin on tuberoinfundibular dopamine neurons; in the absence of STAT5b, the signal transduction in the hypothalamic dopamine neurons is impaired (67).…”

Section: Regulation Of Gh Secretionmentioning

confidence: 94%

“…Patients with GHRHR (116) and GHR mutations are reported to be fertile. Gonadal function of a 30-year-old patient with STAT5b mutation was normal (54). The 55-year-old patient with an inactivating IGF-I gene mutation had a small testicular volume, low inhibin B levels, and elevated FSH levels, indicating compromised Sertoli cell function and impaired spermatogenesis (14).…”

Section: Puberty and Gonadal Functionmentioning

confidence: 97%

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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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“…The JAK2-STAT5B pathway is most important for GH signaling in terms of growth and is also essential in interleukin 2 (IL2)-mediated T-cell signaling, as proven by the severe short stature due to GH insensitivity in combination with immunodeficiency in all patients except one (12) with homozygous STAT5B defects (3,4,5,13,14). The second pathway is the RAS-MAPK signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

A mosaic de novo duplication of 17q21–25 is associated with GH insensitivity, disturbed in vitro CD28-mediated signaling, and decreased STAT5B, PI3K, and NF-κB activation

Mul

Wu²,

Paus³

et al. 2012

European Journal of Endocrinology

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Objective: The established causes of GH insensitivity include defects of the GH receptor and STAT5B. The latter condition is also characterized by severe immunodeficiency. A recent case with short stature, GH resistance, and immunodeficiency due to an IkB mutation suggests that the NF-kB pathway may interact with STAT5B signaling. Design: Here, we present a case of a short child with several congenital anomalies as well as GH insensitivity and mild immunodeficiency associated with a mosaic de novo duplication of chromosome 17q21-25, suggesting that overexpression of one of the duplicated genes may be implicated in GH resistance. Methods and results: In vitro studies on blood lymphocytes showed disturbed signaling of the CD28 pathway, involving NF-kB and related proteins. Functional studies on cultured skin fibroblasts revealed that NF-kB activation, PI3K activity, and STAT5 phosphorylation in response to GH were suppressed, while the sensitivity to GH in terms of MAPK phosphorylation was increased. An in silico analysis of the duplicated genes showed that MAP3K3 and PRKCA are associated with the NF-kB pathway. Baseline MAP3K3 expression in T-cell blasts (TCBs) was normal, but PRKCA expression in TCBs and fibroblasts was significantly higher than that in control cells. Conclusions: We conclude that the 17q21-25 duplication is associated with GH insensitivity and disturbed STAT5B, PI3K, and NF-kB signaling, possibly due to PRKCA mRNA overexpression.

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Clinical and Biochemical Characteristics of a Male Patient with a Novel Homozygous STAT5b Mutation

Cited by 93 publications

References 19 publications

Estrogens in the Control of Growth Hormone Actions in Liver

Estrogens in the Control of Growth Hormone Actions in Liver

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

A mosaic de novo duplication of 17q21–25 is associated with GH insensitivity, disturbed in vitro CD28-mediated signaling, and decreased STAT5B, PI3K, and NF-κB activation

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