Isolated GHD: investigation and implication of JAK/STAT related genes before and after rhGH treatment

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• 作者：Letizia Trovato (1) r> Stefania Riccomagno (1) r> Flavia Prodam (1) r> Giulia Genoni (1) r> Gillian E. Walker (1) r> Stefania Moia (1) r> Simonetta Bellone (1) r> Gianni Bona (1) r>
• 关键词：IGHD ; Gene profile ; GH therapy ; GHR ; Cardiovascular risk ; Inflammation
• 刊名：Pituitary
• 出版年：2012
• 出版时间：December 2012
• 年：2012
• 卷：15
• 期：4
• 页码：482-489
• 全文大小：465KB
• 参考文献：1. Hernández LM, Lee PD, Camacho-Hübner C (2007) Isolated growth hormone deficiency. Pituitary 10(4):351-57 rnal" href="http://dx.doi.org/10.1007/s11102-007-0073-3">CrossRef r> 2. Alatzoglou KS, Turton JP, Kelberman D, Clayton PE, Mehta A, Buchanan C, Aylwin S, Crowne EC, Christesen HT, Hertel NT, Trainer PJ, Savage MO, Raza J, Banerjee K, Sinha SK, Ten S, Mushtaq T, Brauner R, Cheetham TD, Hindmarsh PC, Mullis PE, Dattani MT (2009) Expanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency. J Clin Endocrinol Metab 94(9):3191-199 rnal" href="http://dx.doi.org/10.1210/jc.2008-2783">CrossRef r> 3. Meyer S, Ipek M, Keth A, Minnemann T, von Mach MA, Weise A, Ittner JR, Nawroth PP, Pl?ckinger U, Stalla GK, Tuschy U, Weber MM, Kann PH, German KIMS Board, German KIMS Pharmacogenetics Study Group (2007) Short stature and decreased insulin-like growth factor I (IGF-I)/growth hormone (GH)-ratio in an adult GH-deficient patient pointing to additional partial GH insensitivity due to a R179C mutation of the growth hormone receptor. Growth Horm IGF Res 17(4):307-14 rnal" href="http://dx.doi.org/10.1016/j.ghir.2007.03.001">CrossRef r> 4. Jancevska A, Gucev ZS, Tasic V, Pop-Jordanova N (2009) Growth hormone deficiency (GHD) and small for gestational age (SGA): genetic alterations. Prilozi 30(2):33-5 r> 5. Rosenfeld RG, Belgorosky A, Camacho-Hubner C, Savage MO, Wit JM, Hwa V (2007) Defects in growth hormone receptor signaling. Trends Endocrinol Metab 18(4):134-41 rnal" href="http://dx.doi.org/10.1016/j.tem.2007.03.004">CrossRef r> 6. Lanes R (2004) Long-term outcome of growth hormone therapy in children and adolescents. Treat Endocrinol 3(1):53-6 rnal" href="http://dx.doi.org/10.2165/00024677-200403010-00006">CrossRef r> 7. Jorge AA, Arnhold IJ (2009) Growth hormone receptor exon 3 isoforms and their implication in growth disorders and treatment. Horm Res 71(Suppl 2):55-3 rnal" href="http://dx.doi.org/10.1159/000192438">CrossRef r> 8. Ranke MB, Lindberg A (2009) Predicting growth in response to growth hormone treatment. Growth Horm IGF Res 19:1-1 rnal" href="http://dx.doi.org/10.1016/j.ghir.2008.08.001">CrossRef r> 9. Sesmilo G, Biller BM, Llevadot J, Hayden D, Hanson G, Rifai N, Klibanski A (2000) Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency. A randomized, controlled clinical trial. Ann Intern Med 133(2):111-22 r> 10. Deepak D, Daousi C, Javadpour M, Clark D, Perry Y, Pinkney J, Macfarlane IA (2010) The influence of growth hormone replacement on peripheral inflammatory and cardiovascular risk markers in adults with severe growth hormone deficiency. Growth Horm IGF Res 20(3):220-25 rnal" href="http://dx.doi.org/10.1016/j.ghir.2010.02.002">CrossRef r> 11. Sesmilo G, Fairfield WP, Katznelson L, Pulaski K, Freda PU, Bonert V, Dimaraki E, Stavrou S, Vance ML, Hayden D, Klibanski A (2002) Cardiovascular risk factors in acromegaly before and after normalization of serum IGF-I levels with the GH antagonist pegvisomant. J Clin Endocrinol Metab 87(4):1692-699 rnal" href="http://dx.doi.org/10.1210/jc.87.4.1692">CrossRef r> 12. Cacciari E, Milani S, Balsamo A, Spada E, Bona G, Cavallo L, Cerutti F, Gargantini L, Greggio N, Tonini G, Cicognani A (2006) Italian cross-sectional growth charts for height, weight and BMI (2 to 20?yr). J Endocrinol Invest 29(7):581-93 r> 13. de Jager W, te Velthuis H, Prakken BJ, Kuis W, Rijkers GT (2003) Simultaneous detection of 15 human cytokines in a single sample of stimulated peripheral blood mononuclear cells. Clin Diagn Lab Immunol 10:133-39 r> 14. Andreassen M, Vestergaard H, Kristensen L? (2007) Concentrations of the acute phase reactants high-sensitive C-reactive protein and YKL-40 and of interleukin-6 before and after treatment in patients with acromegaly and growth hormone deficiency. Clin Endocrinol (Oxf) 67(6):909-16 rnal" href="http://dx.doi.org/10.1111/j.1365-2265.2007.02986.x">CrossRef r> 15. Lanes R, Marcano H, Villaroel O, Gunczler P, Morillo E, Paoli M, Perez M, Maulino N, Palacios A (2008) Circulating levels of high-sensitivity C-reactive protein and soluble markers of vascular endothelial cell activation in growth hormone-deficient adolescents. Horm Res 70(4):230-35 rnal" href="http://dx.doi.org/10.1159/000151595">CrossRef r> 16. Szczepańska-Kostro J, Kowalewski M, Urban M, Gardziejczyk M (2006) Serum levels of matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 2 (TIMP-2) in children and adolescents with growth hormone deficiency. Endokrynol Diabetol Chor Przemiany Materii Wieku Rozw 12(4):257-60 r> 17. Pet?j? J (2011) Inflammation and coagulation. An overview. Thromb Res 127(Suppl 2):S34–S37 rnal" href="http://dx.doi.org/10.1016/S0049-3848(10)70153-5">CrossRef r> 18. Mullis PE, O’Donovan N, Eblé A, Marti U, Diem P, Bürgi U, Peter HJ (2000) Growth hormone regulates growth hormone receptor gene transcription in primary human thyroid cells. Mol Cell Endocrinol 166(2):111-19 rnal" href="http://dx.doi.org/10.1016/S0303-7207(00)00272-0">CrossRef r> 19. Bennett WL, Keeton AB, Ji S, Xu J, Messina JL (2007) Insulin regulation of growth hormone receptor gene expression: involvement of both the PI-3 kinase and MEK/ERK signaling pathways. Endocrine 32(2):219-26 rnal" href="http://dx.doi.org/10.1007/s12020-007-9021-2">CrossRef r> 20. Amselem S, Sobrie ML, Duquesnoy P, Rappaport R, Postel-Vinay MC, Gourmelen M, Dallapiccola B, Goossens M (1991) Recurrent nonsense mutations in the Growth Hormone Receptor from patients with Laron Dwarfism. J Clin Invest 87:1098-102 rnal" href="http://dx.doi.org/10.1172/JCI115071">CrossRef r> 21. Dos Santos C, Essioux L, Teinturier C, Tauber M, Goffin V, Bougnères P (2004) A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Nat Genet 36(7):720-24 rnal" href="http://dx.doi.org/10.1038/ng1379">CrossRef r> 22. Barbosa EJ, Palming J, Glad CA, Filipsson H, Koranyi J, Bengtsson BA, Carlsson LM, Boguszewski CL, Johannsson G (2009) Influence of the exon 3-deleted/full-length growth hormone (GH) receptor polymorphism on the response to GH replacement therapy in adults with severe GH deficiency. J Clin Endocrinol Metab 94(2):639-44 rnal" href="http://dx.doi.org/10.1210/jc.2008-0323">CrossRef r> 23. R?z B, Janner M, Petkovic V, Lochmatter D, Eblé A, Dattani MT, Hindmarsh PC, Flück CE, Mullis PE (2008) Influence of growth hormone (GH) receptor deletion of exon 3 and full-length isoforms on GH response and final height in patients with severe GH deficiency. J Clin Endocrinol Metab 93(3):974-80 rnal" href="http://dx.doi.org/10.1210/jc.2007-1382">CrossRef r> 24. Pilotta A, Mella P, Filisetti M, Felappi B, Prandi E, Parrinello G, Notarangelo LD, Buzi F (2006) Common polymorphisms of the growth hormone (GH) receptor do not correlate with the growth response to exogenous recombinant human GH in GH-deficient children. J Clin Endocrinol Metab 91(3):1178-180 rnal" href="http://dx.doi.org/10.1210/jc.2005-1308">CrossRef r> 25. Ihara K, Inuo M, Kuromaru R, Miyako K, Kohno H, Kinukawa N, Hara T (2007) The Leu544Ile polymorphism of the growth hormone receptor gene affects the serum cholesterol levels during GH treatment in children with GH deficiency. Clin Endocrinol (Oxf) 67(2):212-17 rnal" href="http://dx.doi.org/10.1111/j.1365-2265.2007.02863.x">CrossRef r> 26. Lanes R (2004) Metabolic abnormalities in growth hormone deficiency. Pediatr Endocrinol Rev 2(2):209-15 r> 27. Lanes R, Soros A, Flores K, Gunczler P, Carrillo E, Bandel J (2005) Endothelial function, carotid artery intima-media thickness, epicardial adipose tissue, and left ventricular mass and function in growth hormone-deficient adolescents: apparent effects of growth hormone treatment on these parameters. J Clin Endocrinol Metab 90(7):3978-982 rnal" href="http://dx.doi.org/10.1210/jc.2005-0091">CrossRef r>
• 作者单位：Letizia Trovato (1) r> Stefania Riccomagno (1) r> Flavia Prodam (1) r> Giulia Genoni (1) r> Gillian E. Walker (1) r> Stefania Moia (1) r> Simonetta Bellone (1) r> Gianni Bona (1) r>r>1. Division of Pediatrics, Department of Medical Science, University “A. Avogadro-of Piemonte Orientale, Via Solaroli 17, 28100, Novara, Italy r>
• ISSN：1573-7403

文摘

Isolated GH deficiency (IGHD) is a rare disorder that occurs as an idiopathic form in most cases. The pathway JAK/STAT promotes cellular growth and it could be implicated in this condition. In order to characterize IGHD in the pediatric population and identify genes differently expressed before and after GH therapy, we performed a quantitative evaluation of 84 genes related to the JAK/STAT pathway which, by promoting cellular growth. RT2 Profiler PCR Array and the other/subsequent evaluations were performed in three children with severe IGHD before and after 6?months of GH therapy and in three matched normal children. Gene profiling was modified by the IGHD status and the GH therapy, with a modulation of GHR and some inflammatory genes such as CRP. We found a heterozygous nonsense mutation R43X in the GHR gene in two out of three IGHD subjects, despite a good response to therapy. After therapy cardiovascular markers linked to genes as IL6, IL8 and TNF-α displayed a trend toward reduction. Pre- and post therapy status differently affects gene expression. Mutational screening of GHR may be useful in investigating IGHD’s etiology. Genes linked to inflammation suggest to evaluate cardiovascular risks also in pediatric IGHD subjects.