scholarly journals Short stature in two siblings heterozygous for a novel bioinactive GH mutant (GH-P59S) suggesting that the mutant also affects secretion of the wild-type GH

2013 ◽  
Vol 168 (3) ◽  
pp. K35-K43 ◽  
Author(s):  
Vibor Petkovic ◽  
Maria Consolata Miletta ◽  
Annemieke M Boot ◽  
Monique Losekoot ◽  
Christa E Flück ◽  
...  
Keyword(s):  
Short Stature ◽  
Computational Simulation ◽  
Wild Type ◽  
Binding Studies ◽  
Gh Receptor ◽  
Stimulation Tests ◽  
Catch Up ◽  
Severe Short Stature ◽  
Design And Methods

ObjectiveShort stature caused by biologically inactive GH is clinically characterized by lack of GH action despite normal-high secretion of GH, pathologically low IGF1 concentrations and marked catch-up growth on GH replacement therapy.Design and methodsAdopted siblings (girl and a boy) of unknown family history were referred for assessment of short stature (−4.5 and −5.6 SDS) at the age of 10 and 8.1 years respectively. They had delayed bone ages (6.8 and 4.5 years), normal GH peaks at stimulation tests, and severely reduced IGF1 concentrations (−3.5 and −4.0 SDS). Genetic analysis of the GH1 gene showed a heterozygous P59S mutation at position involved in binding to GH receptor (GHR).ResultsIsoelectric focusing analysis of secreted GH in patient serum revealed the presence of higher GH-P59S peak compared with that of wt-GH. Furthermore, computational simulation of GH-P59S binding to GHR suggested problems in correct binding of the mutant to the GHR. In vitro GHR binding studies revealed reduced binding affinity of GH-P59S for GHR (IC50, 30 ng/ml) when compared with the wt-GH (IC50, 11.8 ng/ml) while a significantly decreased ability of the mutant to activate the Jak2/Stat5 signaling pathway was observed at physiological concentrations of 25–100 ng/ml.ConclusionsThe clinical and biochemical data of our patients support the diagnosis of partial bioinactive GH syndrome. The higher amount of GH-P59S secreted in their circulation combined with its impact on the wt-GH function on GHR binding and signaling may alter GHR responsiveness to wt-GH and could ultimately explain severe short stature found in our patients.

scholarly journals Etiology of severe short stature below −3 SDS in a screened Finnish population

2020 ◽  
Vol 183 (5) ◽  
pp. 481-488
Author(s):  
Juho Kärkinen ◽  
Päivi J Miettinen ◽  
Taneli Raivio ◽  
Matti Hero
Keyword(s):  
Short Stature ◽  
University Hospital ◽  
Hormone Deficiency ◽  
Growth Monitoring ◽  
Growth Data ◽  
Target Height ◽  
Hospital District ◽  
Sitting Height ◽  
Catch Up ◽  
Severe Short Stature

Objective: To describe the etiology of severe short stature in the Helsinki University Hospital district covering a population of 1.2 million that is subject to frequent growth monitoring and screening rules during childhood. Design: Retrospective cohort study. Methods: We identified all subjects born 1990 or later with a height SD score <−3, after the age of 3 years, from the Helsinki University Hospital district growth database. A total of 785 subjects (376 females and 409 males) fulfilled our inclusion criteria; we reviewed their medical records and growth data and report their underlying diagnoses. Results: A pathological cause for short stature was diagnosed in 76% of the girls and 71% of the boys (P = NS). Syndromes were the most numerous pathological cause (n = 160; 20%), followed by organ disorders (n = 127; 16%), growth hormone deficiency (GHD, n = 94; 12%), SGA without catch-up growth (n = 73; 9%), and skeletal dysplasias (n = 57; 7%). Idiopathic short stature (ISS) was diagnosed in 210 (27%) subjects. The probability of growth-related pathology, particularly of a syndrome or skeletal dysplasia, increased with the shorter height SD score and the greater deviation from the target height. Sitting height to height SDS was increased in subjects with ISS, GHD, and SGA (all P < 0.01). Conclusions: Height <−3 SDS after 3 years of age usually results from a pathological cause and should be thoroughly investigated in specialized health care. The chance of finding a specific etiology increased with the severity of short stature, and the mismatch with target height.

scholarly journals Leptin stimulates aromatase in the growth plate: limiting catch-up growth efficiency

2018 ◽  
Vol 237 (3) ◽  
pp. 229-242 ◽  
Author(s):  
Majdi Masarwi ◽  
Raanan Shamir ◽  
Moshe Phillip ◽  
Galia Gat-Yablonski
Keyword(s):  
Short Stature ◽  
Growth Plate ◽  
Treatment Strategies ◽  
Young Male ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Epiphyseal Growth Plate ◽  
Catch Up

Catch-up growth (CUG) in childhood is defined as periods of growth acceleration, after the resolution of growth attenuation causes, bringing the children back to their original growth trajectory. Sometimes, however, CUG is incomplete, leading to permanent growth deficit and short stature. The aim of this study was to investigate the mechanisms that limit nutritional-CUG. Specifically, we focused on the crosstalk between leptin, increased by re-feeding, and sex hormones, which increase with age. In vivo studies were performed in young male Sprague Dawley rats fed ad libitum or subjected to 10/36 days of 40% food restriction followed by 90–120 days of re-feeding. In vitro studies were performed on ATDC5 cells. Analyses of mRNA and protein levels were done using qPCR and Western blot, respectively. CUG was complete in body weight and humerus length in animals that were food-restricted for 10 days but not for those food-restricted for 36 days. In vitro studies showed that leptin significantly increased aromatase gene expression and protein level as well as the expression of estrogen and leptin receptors in a dose- and time-dependent manner. The effect of leptin on aromatase was direct and was mediated through the MAPK/Erk, STAT3 and PI3K pathways. The crosstalk between leptin and aromatase in the growth plate suggests that re-feeding during puberty may lead to increased estrogen level and activity, and consequently, irreversible premature epiphyseal growth plate closure. These results may have important implications for the development of novel treatment strategies for short stature in children.

scholarly journals Partial tachyphylaxis to somatostatin (SST) analogues in a patient with acromegaly: the role of SST receptor desensitisation and circulating antibodies to SST analogues

2002 ◽  
pp. 295-302 ◽  
Author(s):  
ST Wahid ◽  
P Marbach ◽  
B Stolz ◽  
M Miller ◽  
RA James ◽  
...  
Keyword(s):  
Time Course ◽  
Radioligand Binding ◽  
Binding Assays ◽  
Binding Studies ◽  
Receptor Signal ◽  
Immune Mediated ◽  
Previously Treated ◽  
Short Time ◽  
Design And Methods

OBJECTIVE: Somatostatin (SST) analogues are a key option in the management of a variety of conditions, including acromegaly. Tachyphylaxis to SST analogues is not documented in acromegaly. We describe such a phenomenon. DESIGN AND METHODS: A 74-year-old female with acromegaly previously treated with (90)Y implant, external radiotherapy and thrice daily s.c. octreotide had stable GH levels of 19 mU/l. GH progressively rose following switches to lanreotide and depot octreotide as Sandostatin LAR: from 29 to 126 mU/l. Magnetic resonance imaging and (111)In-pentetreotide scanning revealed no tumour growth or alteration in SST receptor (SSTR) status. Tachyphylaxis to SST analogues was considered. Therapy was discontinued and re-introduced in daily 200 microg/24 h increments by continuous s.c. infusion, to a maximum of 1000 microg/24 h, and maintained over 3 weeks with daily, followed by weekly, GH profiles. Competitive (125)I-octreotide radioligand binding assays measured in vitro bio-activity of anti-SST analogue antibodies. In vitro SSTR binding studies utilised SSTR-expressing rat cortex membrane. RESULTS: Median GH fell by 93% from 504 to 39.5 mU/l and rose reproducibly on continued infusion to 120 mU/l. Octreotide withdrawal for 16 h produced a 64% increase in sensitivity. High-affinity IgG anti-lanreotide (IC(50)=187 pmol/l) and anti-octreotide (IC(50)=82 nmol/l) antibody, with no crossreactivity with natural SST, was demonstrated. In vitro inhibition of (125)I-octreotide SSTR binding by anti-SST analogue crossreacting antibody was observed at 1:1 serum dilution. CONCLUSIONS: This is the first report of tachyphylaxis to SST analogues in acromegaly. We believe that the short time course of resensitisation following acute octreotide withdrawal is suggestive of an effect(s) on receptor function or on the receptor signal transduction cascade at sites further downstream, rather than an immune-mediated phenomenon.

scholarly journals The D152H mutation found in growth hormone insensitivity syndrome impairs expression and function of human growth hormone receptor but is silent in rat receptor

1998 ◽  
Vol 21 (1) ◽  
pp. 61-72 ◽  
Author(s):  
N Esposito ◽  
J Wojcik ◽  
J Chomilier ◽  
JF Martini ◽  
PA Kelly ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Receptor ◽  
Human Growth ◽  
Receptor Protein ◽  
Wild Type ◽  
Gh Receptor ◽  
293 Cells ◽  
Expression And Activity ◽  
Gh Resistance

In two patients with growth hormone (GH) insensitivity syndrome (Laron syndrome), in whom the GH receptor is able to bind the hormone, the D152H mutation was identified, and lack of dimerization was proposed to explain GH resistance in these patients. To examine further the consequences of the substitution of conserved aspartate 152 on the function of the GH receptor (GHR), we reproduced the mutation in vitro on the full length GH receptor cDNA from man and rat. Effects of the mutation on expression and activity of the GHR were analyzed in 293 cells transfected with wild-type and mutant GHR cDNAs. Mutant human receptor protein was expressed at a lower level than wild-type receptor and its activity was reduced: GH-dependent signal transducer and activator of transcription 5 (Stat5)-mediated transactivation of a reporter gene was lower in 293 cells transfected with mutant GHR cDNA than in transfected cells expressing a comparable level of wild-type GHR. The membrane-bound form of the mutant and of the wild-type human GHR were able to homodimerize, as suggested by the size of the complexes detected in cross-linking experiments with 125I-human (h) GH, and also by the activity in the functional test. With the soluble GHR resulting from proteolysis of the wild-type membrane form, no dimeric complexes could be detected. However, when a soluble receptor lacking the transmembrane and cytoplasmic domains of the receptor was expressed, wild-type and not mutant GH binding protein (GHBP) was able to form dimers in the presence of hGH. The amino acid substitution has no effect on either expression or function of the rat receptor. Structural modeling of D152H soluble human and rat GHR (GHBP) supports the species-specific functional consequences of the mutation. Evaluation of the functional importance of the mutation strongly suggests that impairment in expression and activity of the mutant receptor, rather than complete lack of dimerization, explains the GH resistance of the patients.

A down-regulatable E-selectin ligand is functionally important for PSGL-1–independent leukocyte–endothelial cell interactions

Blood ◽  
2004 ◽  
Vol 104 (12) ◽  
pp. 3766-3773 ◽  
Author(s):  
Renata C. O. Zanardo ◽  
Claudine S. Bonder ◽  
John M. Hwang ◽  
Graciela Andonegui ◽  
Lixin Liu ◽  
...  
Keyword(s):  
Contact Hypersensitivity ◽  
Local Administration ◽  
Wild Type ◽  
Binding Studies ◽  
Tnf Α ◽  
Selectin Ligand ◽  
Factor Α ◽  
Necrosis Factor

P-selectin glycoprotein-1 (PSGL-1) supports P-selectin–dependent rolling in vivo and in vitro. However, controversy exists regarding the importance of PSGL-1–dependent and –independent E-selectin rolling. Using antibodies against PSGL-1 and PSGL-1-/- mice, we demonstrated abolition of P-selectin–dependent rolling but only partial inhibition of E-selectin–mediated rolling in the cremaster microcirculation following local administration of tumor necrosis factor α (TNF-α). In vitro studies demonstrated that binding of recombinant mouse E-selectin chimera to PSGL-1-/- neutrophils was dramatically decreased in mice treated systemically but not locally with TNF-α. Further, PSGL-1 blockade abolished E-selectin–dependent rolling in wild-type mice following systemic TNF-α administration but not local TNF-α administration. Together, these data support an E-selectin ligand present on PSGL-1-/- neutrophils that is down-regulatable upon systemic but not local activation. To determine whether the PSGL-1–independent E-selectin ligand was physiologically important, we used a P- and E-selectin–dependent cutaneous contact hypersensitivity model. Binding studies showed no E-selectin ligand down-regulation in this model. The few cells that rolled on E-selectin ligand following PSGL-1 antibody administration or in PSGL-1 deficiency were sufficient to induce profound contact hypersensitivity. In conclusion, E-selectin mediates PSGL-1–dependent and independent rolling and the latter can be down-regulated by systemic activation and can replace PSGL-1 to support the development of inflammation.

scholarly journals Anti-SARS-CoV-2 Activity of Rhamnan Sulfate from Monostroma nitidum

Marine Drugs ◽  
2021 ◽  
Vol 19 (12) ◽  
pp. 685
Author(s):  
Yuefan Song ◽  
Peng He ◽  
Andre L. Rodrigues ◽  
Payel Datta ◽  
Ritesh Tandon ◽  
...  
Keyword(s):  
Structural Characteristics ◽  
Monosaccharide Composition ◽  
Cell Receptor ◽  
Host Cells ◽  
Health Concern ◽  
Wild Type ◽  
Binding Studies ◽  
S Protein ◽  
Monostroma Nitidum

The COVID-19 pandemic is a major human health concern. The pathogen responsible for COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), invades its host through the interaction of its spike (S) protein with a host cell receptor, angiotensin-converting enzyme 2 (ACE2). In addition to ACE2, heparan sulfate (HS) on the surface of host cells also plays a significant role as a co-receptor. Our previous studies demonstrated that sulfated glycans, such as heparin and fucoidans, show anti-COVID-19 activities. In the current study, rhamnan sulfate (RS), a polysaccharide with a rhamnose backbone from a green seaweed, Monostroma nitidum, was evaluated for binding to the S-protein from SARS-CoV-2 and inhibition of viral infectivity in vitro. The structural characteristics of RS were investigated by determining its monosaccharide composition and performing two-dimensional nuclear magnetic resonance. RS inhibition of the interaction of heparin, a highly sulfated HS, with the SARS-CoV-2 spike protein (from wild type and different mutant variants) was studied using surface plasmon resonance (SPR). In competitive binding studies, the IC50 of RS against the S-protein receptor binding domain (RBD) binding to immobilized heparin was 1.6 ng/mL, which is much lower than the IC50 for heparin (~750 ng/mL). RS showed stronger inhibition than heparin on the S-protein RBD or pseudoviral particles binding to immobilized heparin. Finally, in an in vitro cell-based assay, RS showed strong antiviral activities against wild type SARS-CoV-2 and the delta variant.

The Identification and Significance of a Thr→Pro Polymorphism in Kringle IV Type 8 of Apolipoprotein(a)

1997 ◽  
Vol 77 (05) ◽  
pp. 0949-0954 ◽  
Author(s):  
J Prins ◽  
F R Lues ◽  
Y Y van der Hoek ◽  
J J.P Kastelein ◽  
B N Bouma ◽  
...  
Keyword(s):  
Case Control Study ◽  
Amino Acid Position ◽  
Case Control ◽  
Binding Studies ◽  
Binding Characteristics ◽  
Apolipoprotein A ◽  
Significant Independent Risk Factor ◽  
And Gender ◽  
Control Study

SummaryElevated plasma levels of lipoprotein(a) [Lp(a)] represent a significant independent risk factor for the development of atherosclerosis. Interindividual levels of apo(a) vary over 1000-fold and are mainly due to inheritance that is linked to the locus of the apolipoprotein(a) [apo(a)] gene. The apo(a) gene encodes multiple repeats of a sequence exhibiting up to 85% DNA sequence homology with plasminogen kringle IV (K.IV), a lysine binding domain. In our search for sequence polymorphisms in the K.IV coding domain, we identified a polymorphism predicting a Thr→Pro substitution located at amino acid position 12 of kringle IV type 8 of apo(a). The functional and clinical significance of this polymorphism was analysed in a case-control study and by comparing the in vitro lysine binding characteristics of the two Lp(a) subtypes.The case-control study (involving 153 subjects having symptomatic atherosclerosis and 153 age and gender matched normolipidemic controls) revealed an overall allele frequency for the Thr12-→Pro substitution in kringle IV type 8 of 14% and a negative association between presence of the Pro12-subtype and symptomatic atherosclerosis (p <0.03). The in vitro lysine binding studies, using Lp(a) isolated from subjects homozygous for either Thr12 or Pro12 in K.IV type 8, revealed comparable lysine-Sepharose binding fractions for the two subtypes. The binding affinity (Kd) for immobilised plasmin degraded des- AA-fibrin (DesafibTM-X) was also comparable for the two subtypes, however a decreased maximal attainable binding (Bmax) for immobilised desafibTM-X was observed for the Pro12-subtype Lp(a).

Growth hormone therapy in a child with severe short stature due to Miller-McKusick-Malvaux (3M) syndrome-2

2019 ◽  
Author(s):  
Sumudu Seneviratne ◽  
Deepthi de Silva ◽  
Emily Cottrell ◽  
Piumi Kuruppu ◽  
KSH de Silva ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Hormone Therapy ◽  
Short Stature ◽  
Growth Hormone Therapy ◽  
Severe Short Stature

The URNA Genes of Herpesvirus Saimiri (Strain C488) Are Dispensable for Transformation of Human T Cells In Vitro

1999 ◽  
Vol 73 (12) ◽  
pp. 10551-10555 ◽  
Author(s):  
Armin Ensser ◽  
André Pfinder ◽  
Ingrid Müller-Fleckenstein ◽  
Bernhard Fleckenstein
Keyword(s):  
Cell Culture ◽  
Herpesvirus Saimiri ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Human T Cell ◽  
Human T Cells ◽  
Small Nuclear Rnas ◽  
T Cell Lines

ABSTRACT The herpesvirus saimiri strain C488 genome contains five genes for small nuclear RNAs, termed herpesvirus saimiri URNAs (or HSURs). Using a cosmid-based approach, all HSURs were precisely deleted from the genome. The mutant virus replicated at levels that were similar to those of wild-type viruses in OMK cells. Although the HSURs are expressed in wild-type virus-transformed human T-cell lines, the deletion does not affect viral transformation in cell culture.

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