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Gene Review

GHS  -  Goldenhar syndrome

Homo sapiens

 
 
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Disease relevance of GHS

 

Psychiatry related information on GHS

  • Overall, the GHS core survey and its mental health supplement provide the mental health research community with complex data that allow for high-quality analysis of mental disorders and associations with somatic disorders [5].
  • Although the GHS failed to differentiate elderly persons by age, it was nonetheless related to self-esteem, depression, self-rated health, internality, morale, and life satisfaction [6].
  • Taking into account its orexigenic effect, GHS analogues acting as agonists or antagonists on appetite could represent new drug intervention in eating disorders [7].
  • South Carolina's Greenville Hospital System (GHS) minimizes caregivers' exposure to blood and body fluid through a risk-reduction program that hinges on feedback from data analysis and frontline staff [8].
  • Two girls with concomitant Goldenhar syndrome (oculo-auriculovertebral spectrum disorder) and autistic disorder are described [9].
 

High impact information on GHS

  • Remarkably, the GHS act through all four mechanisms to reproduce a young adult physiological GH profile in elderly subjects that was accompanied by increased bone mineral density and lean mass, modest improvements in strength, and improved recovery from hip fracture [10].
  • We also present evidence that in rare cases SALL1 mutations can lead to phenotypes similar to Goldenhar syndrome [11].
  • A study of the peripheral distribution of GHS receptors has shown that it is also present in cardiovascular tissue, which has led to the exploration of the cardiovascular functions of ghrelin and synthetic, growth-hormone-releasing peptides [12].
  • This finding correlates with the in vivo ACTH hyperresponsiveness to hexarelin (a GHS) [13].
  • To this goal, we compared the effects of ghrelin, hexarelin, a synthetic GHS, or placebo on insulin and glucose as well as on GH levels in 11 normal young volunteers (age [mean +/- SEM]: 28.5 +/- 3.1 yr; BMI: 22.2 +/- 0.9 Kg/m(2)) [14].
 

Chemical compound and disease context of GHS

 

Biological context of GHS

  • [125I-His(9)]-ghrelin, a novel radioligand for localizing GHS orphan receptors in human and rat tissue: up-regulation of receptors with athersclerosis [19].
  • The likely existence of GHS-R subtypes and evidence that the neuroendocrine actions, but not all the other actions, of ghrelin depend on its acylation in serine-3 revealed a system whose complexity had not been completely explored by studying synthetic GHS [20].
  • We are now confronted with the theoretical possibility that GHS analogues could become candidate drugs for treatment of pathophysiological conditions in internal medicine totally unrelated to disorders of GH secretion [21].
  • In conclusion, we have demonstrated a dose-dependent and specific stimulation of cardiomyocyte thymidine incorporation by natural and synthetic GHS analogues, suggesting increased cell proliferation and binding of GHS to H9c2 cardiomyocyte cell membranes [22].
  • It is shown that the procedure will be completed with considerably less death and suffering than guideline 402, and will classify substances either in the same or a more stringent GHS class than that assigned on the basis of the LD50 value [23].
 

Anatomical context of GHS

  • The family of GH secretagogues (GHS) includes synthetic peptidyl (hexarelin) and nonpeptidyl (MK-0677) molecules possessing specific receptors in the pituitary and central nervous system as well as in peripheral tissues, including the heart and some endocrine organs [1].
  • The presence of specific GHS binding sites was also demonstrated in three different human breast carcinoma cell lines (MCF7, T47D, and MDA-MB231), in which, surprisingly, no messenger RNA for GHS-R1a was demonstrated by RT-PCR [1].
  • The family of GH secretagogues (GHS) includes peptidyl (hexarelin) and nonpeptidyl (MK 0677) molecules possessing specific receptors in the brain, pituitary, and thyroid [24].
  • GHS receptors were detected mainly in the myocardium, but they were also present (in order of decreasing binding activity) in adrenal, gonads, arteries, lung, liver, skeletal muscle, kidney, pituitary, thyroid, adipose tissue, veins, uterus, skin, and lymphnode [24].
  • The amount of total body and abdominal fat mass throughout the study and the increment in these masses were more marked in the GHD than in the GHS and control subjects when GH treatment was discontinued [25].
 

Associations of GHS with chemical compounds

  • Aim of our study was to verify the antagonistic action of d-Lys-GHRP-6 on the endocrine responses to acylated ghrelin and hexarelin, a peptidyl synthetic GHS, in humans [26].
  • Twenty-four hours from the acute bolus injection of testosterone, C(max) and AUC(0-90) of the GHS-stimulated cGH response were significantly lower than baseline cGH response; 5 days later, there was still a significant decrease of either parameter versus the original values [27].
  • GH responsiveness to GH secretagogues (GHS) is blunted in Cushing's disease (CD), while ACTH/cortisol responses are enhanced, by mechanisms still unclear [28].
  • Both before and 2 yr after GH treatment was discontinued, serum concentrations of total cholesterol (C), low density lipoprotein C, and apolipoprotein B were higher in the GHD than in both GHS and control subjects [25].
  • OBJECTIVE: Ghrelin, a 28-amino-acid peptide purified from the stomach and showing a unique structure with an n-octanoyl ester at the serine 3 residue, is a natural ligand of the GH secretagogue (GHS) receptor (GHS-R) [29].
 

Physical interactions of GHS

  • Oculo-auriculo-vertebral (OAV) spectrum or Goldenhar syndrome is a complex and heterogeneous condition characterized by hemifacial microsomia (unilateral ear abnormalities and ipsilateral mandibular hypoplasia) as well as vertebral anomalies and epibulbar dermoids or lipodermoids [30].
 

Other interactions of GHS

  • GHSs are very effective for enhancing GH secretion in old subjects, but long-term studies are needed to assess their safety and the real biological impact of GHS replacement therapy in aging [31].
  • Ghrelin strongly stimulates GH secretion in both animals and humans, showing a synergistic effect with GH-releasing hormone (GHRH) but no interaction with synthetic GHS [29].
  • Targeting the ghrelin receptor: orally active GHS and cortistatin analogs [32].
  • The PRL releasing activity of GHS probably comes from direct pituitary action, which indeed is slight and independent of both age and gender [33].
  • These cells also expressed SRIF receptors types 2, 3 and 5, ghrelin and GHS receptors [34].
 

Analytical, diagnostic and therapeutic context of GHS

  • Using site-directed mutagenesis and molecular modeling, we classified GHS peptide and nonpeptide agonist binding in the context of its receptor environment [35].
  • Our aim was to investigate the presence of GHS receptors in a wide range of human tissues, by radioreceptor assay with [125I]Tyr-Ala-hexarelin [24].
  • Ghrelin, the endogenous ligand of the growth hormone (GH) secretagogue (GHS) receptor and some GHSs exert different effects on sleep electroencephalogram (EEG) and sleep-related hormone secretion in humans [36].
  • RESULTS: The GHS patients (n = 16) were younger (P < 0.01), had lower baseline cortisol levels [255 +/- 37 vs. 372 +/- 38 nmol/l (P = 0.04)], and tended to have a lower body mass index (P = 0.09) as compared to GHD patients (n = 25) [37].
  • In 7 male volunteers, we studied cardiac performance by radionuclide angiocardiography after iv administration of rhGH or hexarelin (HEX), a peptidyl GHS [38].

References

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  2. Ghrelin promotes slow-wave sleep in humans. Weikel, J.C., Wichniak, A., Ising, M., Brunner, H., Friess, E., Held, K., Mathias, S., Schmid, D.A., Uhr, M., Steiger, A. Am. J. Physiol. Endocrinol. Metab. (2003) [Pubmed]
  3. Alprazolam, a benzodiazepine, blunts but does not abolish the ACTH and cortisol response to hexarelin, a GHRP, in obese patients. Grottoli, S., Arvat, E., Gauna, C., Maccagno, B., Ramunni, J., Giordano, R., Maccario, M., Deghenghi, R., Ghigo, E. Int. J. Obes. Relat. Metab. Disord. (2000) [Pubmed]
  4. Gordon Holmes spinocerebellar ataxia: a gonadotrophin deficiency syndrome resistant to treatment with pulsatile gonadotrophin-releasing hormone. Quinton, R., Barnett, P., Coskeran, P., Bouloux, P.M. Clin. Endocrinol. (Oxf) (1999) [Pubmed]
  5. Estimating the prevalence of mental and somatic disorders in the community: aims and methods of the German National Health Interview and Examination Survey. Jacobi, F., Wittchen, H.U., Hölting, C., Sommer, S., Lieb, R., Höfler, M., Pfister, H. International journal of methods in psychiatric research. (2002) [Pubmed]
  6. Hopelessness in community-residing aged persons: a viable construct? Hayslip, B., Lopez, F.G., Nation, P. Journal of personality assessment. (1991) [Pubmed]
  7. Central and peripheral activities of ghrelin, a ligand of the growth hormone secretagogue receptor. Bona, G., Bellone, S. Panminerva medica. (2003) [Pubmed]
  8. The safety needle switchover, part 2 of 2. Steed, C., Baker, M. Nursing management. (2002) [Pubmed]
  9. Goldenhar syndrome and autistic behaviour. Landgren, M., Gillberg, C., Strömland, K. Developmental medicine and child neurology. (1992) [Pubmed]
  10. Development of growth hormone secretagogues. Smith, R.G. Endocr. Rev. (2005) [Pubmed]
  11. Molecular analysis of SALL1 mutations in Townes-Brocks syndrome. Kohlhase, J., Taschner, P.E., Burfeind, P., Pasche, B., Newman, B., Blanck, C., Breuning, M.H., ten Kate, L.P., Maaswinkel-Mooy, P., Mitulla, B., Seidel, J., Kirkpatrick, S.J., Pauli, R.M., Wargowski, D.S., Devriendt, K., Proesmans, W., Gabrielli, O., Coppa, G.V., Wesby-van Swaay, E., Trembath, R.C., Schinzel, A.A., Reardon, W., Seemanova, E., Engel, W. Am. J. Hum. Genet. (1999) [Pubmed]
  12. Effects of ghrelin and synthetic GH secretagogues on the cardiovascular system. Cao, J.M., Ong, H., Chen, C. Trends Endocrinol. Metab. (2006) [Pubmed]
  13. Cyclical Cushing's syndrome in a patient with a bronchial neuroendocrine tumor (typical carcinoid) expressing ghrelin and growth hormone secretagogue receptors. Arnaldi, G., Mancini, T., Kola, B., Appolloni, G., Freddi, S., Concettoni, C., Bearzi, I., Masini, A., Boscaro, M., Mantero, F. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  14. Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. Broglio, F., Arvat, E., Benso, A., Gottero, C., Muccioli, G., Papotti, M., van der Lely, A.J., Deghenghi, R., Ghigo, E. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  15. Effects of alprazolam, a benzodiazepine, on the ACTH-, GH- and PRL-releasing activity of hexarelin, a synthetic peptidyl GH secretagogue (GHS), in patients with simple obesity and in patients with Cushing's disease. Grottoli, S., Arvat, E., Gauna, C., Maccagno, B., Ramunni, J., Giordano, R., Maccario, M., Deghenghi, R., Ghigo, E. Pituitary (1999) [Pubmed]
  16. Ghrelin, hypothalamus-pituitary-adrenal (HPA) axis and Cushing's syndrome. Giordano, R., Picu, A., Broglio, F., Bonelli, L., Baldi, M., Berardelli, R., Ghigo, E., Arvat, E. Pituitary (2004) [Pubmed]
  17. Autism associated with conditions characterized by developmental errors in early embryogenesis: a mini review. Miller, M.T., Strömland, K., Ventura, L., Johansson, M., Bandim, J.M., Gillberg, C. Int. J. Dev. Neurosci. (2005) [Pubmed]
  18. Goldenhar syndrome, anterior encephalocele, and aqueductal stenosis following fetal primidone exposure. Gustavson, E.E., Chen, H. Teratology (1985) [Pubmed]
  19. [125I-His(9)]-ghrelin, a novel radioligand for localizing GHS orphan receptors in human and rat tissue: up-regulation of receptors with athersclerosis. Katugampola, S.D., Pallikaros, Z., Davenport, A.P. Br. J. Pharmacol. (2001) [Pubmed]
  20. Ghrelin: more than a natural GH secretagogue and/or an orexigenic factor. Ghigo, E., Broglio, F., Arvat, E., Maccario, M., Papotti, M., Muccioli, G. Clin. Endocrinol. (Oxf) (2005) [Pubmed]
  21. Neuroendocrine and peripheral activities of ghrelin: implications in metabolism and obesity. Muccioli, G., Tschöp, M., Papotti, M., Deghenghi, R., Heiman, M., Ghigo, E. Eur. J. Pharmacol. (2002) [Pubmed]
  22. Natural (ghrelin) and synthetic (hexarelin) GH secretagogues stimulate H9c2 cardiomyocyte cell proliferation. Pettersson, I., Muccioli, G., Granata, R., Deghenghi, R., Ghigo, E., Ohlsson, C., Isgaard, J. J. Endocrinol. (2002) [Pubmed]
  23. Statistical evaluation of an acute dermal toxicity test using the dermal fixed dose procedure. Stallard, N., Whitehead, A., Indans, I. Human & experimental toxicology. (2004) [Pubmed]
  24. Growth hormone secretagogue binding sites in peripheral human tissues. Papotti, M., Ghè, C., Cassoni, P., Catapano, F., Deghenghi, R., Ghigo, E., Muccioli, G. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  25. Discontinuation of growth hormone (GH) treatment: metabolic effects in GH-deficient and GH-sufficient adolescent patients compared with control subjects. Swedish Study Group for Growth Hormone Treatment in Children. Johannsson, G., Albertsson-Wikland, K., Bengtsson, B.A. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  26. d-Lys-GHRP-6 does not modify the endocrine response to acylated ghrelin or hexarelin in humans. Benso, A., Prodam, F., Lucatello, B., Gramaglia, E., Riganti, F., Schneider, H., van der Lely, A.J., Muccioli, G., Ghigo, E., Broglio, F. Neuropeptides (2007) [Pubmed]
  27. Testosterone inhibition of growth hormone release stimulated by a growth hormone secretagogue. Studies in the rat and dog. Rigamonti, A.E., Cella, S.G., Giordani, C., Bonomo, S.M., Giunta, M., Sartorio, A., Muller, E. Neuroendocrinology (2006) [Pubmed]
  28. Decreased GH secretion and enhanced ACTH and cortisol release after ghrelin administration in Cushing's disease: Comparison with GH-releasing peptide-6 (GHRP-6) and GHRH. Correa-Silva, S.R., Nascif, S.O., Lengyel, A.M. Pituitary (2006) [Pubmed]
  29. The GH-releasing effect of ghrelin, a natural GH secretagogue, is only blunted by the infusion of exogenous somatostatin in humans. Di Vito, L., Broglio, F., Benso, A., Gottero, C., Prodam, F., Papotti, M., Muccioli, G., Dieguez, C., Casanueva, F.F., Deghenghi, R., Ghigo, E., Arvat, E. Clin. Endocrinol. (Oxf) (2002) [Pubmed]
  30. Oculo-auriculo-vertebral (Goldenhar) spectrum associated with pericentric inversion 9: coincidental findings or etiologic factor? Stanojević, M., Stipoljev, F., Koprcina, B., Kurjak, A. J. Craniofac. Genet. Dev. Biol. (2000) [Pubmed]
  31. GH-related and extra-endocrine actions of GH secretagogues in aging. Muller, E.E., Rigamonti, A.E., Colonna, V.d.e. .G., Locatelli, V., Berti, F., Cella, S.G. Neurobiol. Aging (2002) [Pubmed]
  32. Targeting the ghrelin receptor: orally active GHS and cortistatin analogs. Deghenghi, R., Broglio, F., Papotti, M., Muccioli, G., Ghigo, E. Endocrine (2003) [Pubmed]
  33. Endocrine and non-endocrine activities of growth hormone secretagogues in humans. Ghigo, E., Arvat, E., Broglio, F., Giordano, R., Gianotti, L., Muccioli, G., Papotti, M., Graziani, A., Bisi, G., Deghenghi, R., Camanni, F. Horm. Res. (1999) [Pubmed]
  34. Presence of cortistatin in the human pancreas. Papotti, M., Tarabra, E., Allia, E., Bozzalla-Cassione, F., Broglio, F., Deghenghi, R., Ghigo, E., Muccioli, G. J. Endocrinol. Invest. (2003) [Pubmed]
  35. Structural requirements for the activation of the human growth hormone secretagogue receptor by peptide and nonpeptide secretagogues. Feighner, S.D., Howard, A.D., Prendergast, K., Palyha, O.C., Hreniuk, D.L., Nargund, R., Underwood, D., Tata, J.R., Dean, D.C., Tan, C.P., McKee, K.K., Woods, J.W., Patchett, A.A., Smith, R.G., Van der Ploeg, L.H. Mol. Endocrinol. (1998) [Pubmed]
  36. Hexarelin decreases slow-wave sleep and stimulates the secretion of GH, ACTH, cortisol and prolactin during sleep in healthy volunteers. Frieboes, R.M., Antonijevic, I.A., Held, K., Murck, H., Pollmächer, T., Uhr, M., Steiger, A. Psychoneuroendocrinology (2004) [Pubmed]
  37. Serum ghrelin levels are suppressed in hypopituitary patients following insulin-induced hypoglycaemia irrespective of GH status. Ryber, L., Obrink, K., Houe, N., Frystyk, J., Jørgensen, J.O. Clin. Endocrinol. (Oxf) (2006) [Pubmed]
  38. Acute cardiovascular and hormonal effects of GH and hexarelin, a synthetic GH-releasing peptide, in humans. Bisi, G., Podio, V., Valetto, M.R., Broglio, F., Bertuccio, G., Del Rio, G., Arvat, E., Boghen, M.F., Deghenghi, R., Muccioli, G., Ong, H., Ghigo, E. J. Endocrinol. Invest. (1999) [Pubmed]
 
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