Entity

Time filter

Source Type

Cincinnati, OH, United States

Scalco R.C.,University of Sao Paulo | Hwa V.,Cincinnati Center for Growth Disorders | Domene H.M.,CONICET | Jasper H.G.,CONICET | And 7 more authors.
European Journal of Endocrinology | Year: 2015

Context and objective: GH insensitivity with immune dysfunction caused by STAT5B mutations is an autosomal recessive condition. Heterozygous mutations in other genes involved in growth regulation were previously associated with a mild height reduction. Our objective was to assess for the first time the phenotype of heterozygous STAT5B mutations. Methods: We genotyped and performed clinical and laboratory evaluations in 52 relatives of two previously described Brazilian brothers with homozygous STAT5B c.424-427del mutation (21 heterozygous). Additionally, we obtained height data and genotype from 1104 adult control individuals from the same region in Brazil and identified five additional families harboring the same mutation (18 individuals, 11 heterozygous). Furthermore, we gathered the available height data from first-degree relatives of patients with homozygous STAT5B mutations (17 individuals from seven families). Data from heterozygous individuals and non-carriers were compared. Results: Individuals carrying heterozygous STAT5B c.424-427del mutation were 0.6 SDS shorter than their non-carrier relatives (P=0.009). Heterozygous subjects also had significantly lower SDS for serum concentrations of IGF1 (P=0.028) and IGFBP3 (P=0.02) than their non-carrier relatives. The 17 heterozygous first-degree relatives of patients carrying homozygous STAT5B mutations had an average height SDS of K1.4±0.8 when compared with population-matched controls (P< 0.001). Conclusions: STAT5B mutations in the heterozygous state have a significant negative impact on height (w3.9 cm). This effect is milder than the effect seen in the homozygous state, with height usually within the normal range. Our results support the hypothesis that heterozygosity of rare pathogenic variants contributes to normal height heritability. © 2015 The authors.


Wilhelm C.J.,VA Portland Health Care System | Wilhelm C.J.,University of Oregon | Hashimoto J.G.,VA Portland Health Care System | Hashimoto J.G.,University of Oregon | And 5 more authors.
Brain Pathology | Year: 2016

Chronic alcohol abuse is associated with brain damage in a sex-specific fashion, but the mechanisms involved are poorly described and remain controversial. Previous results have suggested that astrocyte gene expression is influenced by ethanol intoxication and during abstinence in vivo. Here, bioinformatic analysis of astrocyte-enriched ethanol-regulated genes in vivo revealed ubiquitin pathways as an ethanol target, but with sexually dimorphic cytokine signaling and changes associated with brain aging in females and not males. Consistent with this result, astrocyte activation was observed after exposure in female but not male animals, with reduced S100β levels in the anterior cingulate cortex and increased GFAP+ cells in the hippocampus. In primary culture, the direct effects of chronic ethanol exposure followed by recovery on sex-specific astrocyte function were examined. Male astrocyte responses were consistent with astrocyte deactivation with reduced GFAP expression during ethanol exposure. In contrast, female astrocytes exhibited increased expression of Tnf, reduced expression of the neuroprotective cytokine Tgfb1, disrupted bioenergetics and reduced excitatory amino acid uptake following exposure or recovery. These results indicate widespread astrocyte dysfunction in ethanol-exposed females and suggest a mechanism that may underlie increased vulnerability to ethanol-induced neurotoxicity in females. © 2015 International Society of Neuropathology


Hwa V.,Cincinnati Center for Growth Disorders
Growth Hormone and IGF Research | Year: 2015

Growth hormone (GH) promotes postnatal human growth primarily by regulating insulin-like growth factor (IGF)-I production through activation of the GH receptor (GHR)-signal transducer and activator of transcription (STAT)-5B signaling cascade. The critical importance of STAT5B in human IGF-I production was confirmed with the identification of the first homozygous, autosomal recessive, STAT5B mutation in a young female patient who phenotypically resembled patients with classical growth hormone insensitivity (GHI) syndrome (Laron syndrome) due to mutations in the GHR gene, presenting with severe postnatal growth failure and marked IGF-I deficiency. Of note, the closely related STAT5A, which shares >. 95% amino acid identity with STAT5B, could not compensate for loss of functional STAT5B. To date, 7 homozygous, inactivating, STAT5B mutations in 10 patients have been reported. STAT5B deficient patients, unlike patients deficient in GHR, can also present with a novel, potentially fatal, primary immunodeficiency, which can manifest as chronic pulmonary disease. STAT5B deficiency may be underestimated in endocrine, immunology and pulmonary clinics. © 2015.


Hershkovitz O.,Biologics | Bar-Ilan A.,Biologics | Guy R.,Biologics | Felikman Y.,Biologics | And 5 more authors.
Molecular Pharmaceutics | Year: 2016

MOD-4023 is a novel long-acting version of human growth hormone (hGH), containing the carboxy-terminal peptide (CTP) of human chorionic gonadotropin (hCG). MOD-4023 is being developed as a treatment for adults and children with growth hormone deficiency (GHD), which would require fewer injections than currently available GH formulations and thus reduce patient discomfort and increase compliance. This study characterizes MOD-4023's binding affinities for the growth hormone receptor, as well as the pharmacokinetic and pharmacodynamics, toxicology, and safety profiles of repeated dosing of MOD-4023 in Sprague-Dawley rats and Rhesus monkeys. Although MOD-4023 exhibited reduced in vitro potency and lower affinity to the GH receptor than recombinant hGH (rhGH), administration of MOD-4023 every 5 days in rats and monkeys resulted in exposure comparable to daily rhGH, and the serum half-life of MOD-4023 was significantly longer. Repeated administration of MOD-4023 led to elevated levels of insulin-like growth factor 1 (IGF-1), and twice-weekly injections of MOD-4023 resulted in larger increase in weight gain with fewer injections and a lower accumulative hGH dose. Thus, the increased half-life of MOD-4023 in comparison to hGH may increase the frequency of protein-receptor interactions and compensate for its decreased in vitro potency. MOD-4023 was found to be well-tolerated in rats and monkeys, with minimal adverse events, suggesting an acceptable safety profile. These results provide a basis for the continued clinical development of MOD-4023 as a novel treatment of GHD in children and adults. © 2015 American Chemical Society.


Baron J.,U.S. National Institutes of Health | Savendahl L.,Karolinska Institutet | De Luca F.,Saint Christophers Hospital for Children | Dauber A.,Cincinnati Center for Growth Disorders | And 3 more authors.
Nature Reviews Endocrinology | Year: 2015

In the past, the growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis was often considered to be the main system that regulated childhood growth and, therefore, determined short stature and tall stature. However, findings have now revealed that the GH-IGF-1 axis is just one of many regulatory systems that control chondrogenesis in the growth plate, which is the biological process that drives height gain. Consequently, normal growth in children depends not only on GH and IGF-1 but also on multiple hormones, paracrine factors, extracellular matrix molecules and intracellular proteins that regulate the activity of growth plate chondrocytes. Mutations in the genes that encode many of these local proteins cause short stature or tall stature. Similarly, genome-wide association studies have revealed that the normal variation in height seems to be largely due to genes outside the GH-IGF-1 axis that affect growth at the growth plate through a wide variety of mechanisms. These findings point to a new conceptual framework for understanding short and tall stature that is centred not on two particular hormones but rather on the growth plate, which is the structure responsible for height gain. © 2015 Macmillan Publishers Limited. All rights reserved NATURE .

Discover hidden collaborations