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Molecular diagnosis of the alterations in the GHRH-GH-IGF-1 axis in patients with short stature

Grant number: 00/14092-4
Support type:Research Projects - Thematic Grants
Duration: October 01, 2001 - September 30, 2006
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal researcher:Ivo Jorge Prado Arnhold
Grantee:Ivo Jorge Prado Arnhold
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Pesquisadores principais:
Ana Claudia Latronico Xavier ; Berenice Bilharinho de Mendonça


Short stature is a common disorder, however, the etiology is established in only a small fraction of cases. Somatic growth depends on the normal synthesis and action of growth hormone (GH). Several genes are involved in the pituitary organogenesis (HESX1, LHX-3, PROP-1), in GH synthesis (GHRHR, GH-1) and in GH action (GHR), and therefore regulate GH synthesis and action determining stature. Mutations in these genes determine the different etiologies of genetic short stature, but there is no specific clinical presentation for each defect. Short stature is also present in genetic syndromes, some with response to recombinant GH treatment. However the cause of short stature in these syndromic patients has not been determined yet. Recent discoveries in the human genome and improvements of molecular biology techniques allow the identification of genetic causes responsible for failure in GH production and action. The exact determination of the etiology of short stature caused by isolated or combined pituitary GH deficiency, or due to genetic syndromes is fundamental to our understanding of anterior pituitary gland development and gene regulation in the GHRH-GH-IGF-I axis. The etiologic diagnosis allows genetic counseling and a more precise prognosis of the disease. The identification of new mutations also enables the study of the importance of specific residues in the structure and function of the protein. During the last 20 years, we have diagnosed and treated children with short stature and we have collected 220 DNA samples, that can be studied for alterations in several genes involved in GH secretion and action. We published reports on Brazilian patients affected by GH-1 deletion and PROP-1 mutations in collaboration with Dr. John Phillips III from Nashiville, Tennessee(1,2), and PIT-1 mutation in collaboration with Dr John Parks from Atlanta, Georgia (3). Recently, we identified a new PROP-1 mutation in our Laboratory, but the functional studies were done in collaboration with Dr. Peter Kopp from Chicago, Illinois(4). We present here six research projects that seek the understanding of pituitary organogenesis, GHRH receptor, GH and GH receptor function, and genetic syndromes that have short stature as a common feature. The aim of this project is to increase our capacity to identify mutations in genes involved in short stature (Figure 1) and perform functional studies of these mutations, such as reporter gene transactivation (luciferase assay), protein-protein interaction (electrophoresis mobility shift assay) and splicing assay. The future discovery of new genes involved in pituitary organogenesis and GH-IGF-I axis during the development of this project will allow expansion through new projects studying our patients whose molecular etiology was not identified by the initial projects. Subproject 1- Molecular study of the HESX-1 gene in patients with GH deficiency associated to cerebral or facial midline defects; Subproject 2- Molecular study of the LHX3 gene in children with combined pituitary hormone deficiency; Subproject 3- Study of PROP-1 gene mutations in patients with combined pituitary hormone deficiency; Subproject 4- Molecular study of the GHRH receptor (GHRHR) and GH-1 genes in patients with isolated GH deficiency; Subproject 5- Molecular study of GH receptor (GHR) in children with short stature due to a probable primary insensitivity to GH; Subproject 6- Study of SHOX gene mutations in patients with idiopathic short stature and Noonan syndrome. References 1. Arnhold, I.J.P.; Osorio, M.G.F.; Oliveira, S.B.; Estefan, V.; Kamijo, T.; Krishnamani, M.R.S.; Cogan, J.D. 1998 Clinical And Molecular Characterization Of Brazilian Patients With Growth Hormone Gene Deletions. Brazilian Journal of Medical and Biological Research 31, 491 - 97.2. Cogan J.D., Wu W., Phillips, III J.A., Arnhold I.J.P., Agapito A., Fofanova V., Osorio M.G.F., Bircan I., Moreno A., Mendonca B.B. 1998 The PROP1 2-Base Pair Deletion is a Common Cause of Combined Pituitary Hormone Deficiency J. Clin. Endocrinol. Metab. 83: 3346-3349.3. Arnhold, I.J.P.; Nery, M.; Brown, M.R.; Voss, B.S.; VanderHeyden, M.S.; Addess, M.E.; Hurley, D.L.; Wajchenberg, M.D.; Parks, J.S. 1998 Clinical and Molecular Characterization of Brazilian Patient with Pit-1 Deficiency. J Pediatr Endocrinol. Metab. 11, 623-630.4. Osorio M.G.F., Kopp P., Marui S., Latronico A.C., Mendonca B.B., Arnhold I.J.P. 2000. Combined Pituitary Hormone Deficiency Caused by a Novel Mutation of a Highly Conserved Residue (F88S) in the Homeodomain of PROP-1. J Clin Endocrin Metab. 85 2779-2785. (AU)

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Scientific publications (6)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MARUI, SUEMI; TRARBACH, ERICKA B.; BOGUSZEWSKI, MARGARET C. S.; FRANCA, MARCELA M.; JORGE, ALEXANDER A. L.; INOUE, HIROSHI; NISHI, MIRIAN Y.; DE LACERDA FILHO, LUIZ; AGUIAR-OLIVEIRA, MANUEL H.; MENDONCA, BERENICE B.; et al. GH-Releasing Hormone Receptor Gene: A Novel Splice-Disrupting Mutation and Study of Founder Effects. Hormone Research in Paediatrics, v. 78, n. 3, p. 165-172, . (00/14092-4)
JORGE, ALEXANDER A. L.; SOUZA, SILVIA C.; NISHI, MIRIAM Y.; BILLERBECK, ANA E.; LIBÓRIO, DÉBORA C. C.; KIM, CHONG A.; ARNHOLD, IVO J. P.; MENDONÇA, BERENICE B.. SHOX mutations in idiopathic short stature and Leri-Weill dyschondrosteosis: frequency and phenotypic variability. Clinical Endocrinology, v. 66, n. 1, p. 130-135, . (00/14092-4)
MELO‚ M.E.; MARUI‚ S.; CARVALHO‚ L.R.; ARNHOLD‚ I.J.P.; LEITE‚ C.C.; MENDONÇA‚ B.B.; KNOEPFELMACHER‚ M.. Hormonal‚ pituitary magnetic resonance‚ LHX4 and HESX1 evaluation in patients with hypopituitarism and ectopic posterior pituitary lobe. Clinical Endocrinology, v. 66, n. 1, p. 95-102, . (00/14092-4)
LIZE V. FERREIRA; SILVIA A.L. SOUZA; LUCIANA R. MONTENEGRO; IVO J.P. ARNHOLD; TITANIA PASQUALINI; JUAN JORGE HEINRICH; ANA CLAUDIA KESELMAN; BERENICE B. MENDONÇA; ALEXANDER A.L. JORGE. Variabilidade do fenótipo de pacientes com síndrome de Noonan com e sem mutações no gene PTPN11. Arquivos Brasileiros de Endocrinologia e Metabologia, v. 51, n. 3, p. 450-456, . (00/14092-4)
JORGE, ALEXANDER A. L.; MARCHISOTTI, FREDERICO G.; MONTENEGRO, LUCIANA R.; CARVALHO, LUCIANI R.; MENDONÇA, BERENICE B.; ARNHOLD, IVO J. P.. Growth hormone (GH) pharmacogenetics: influence of GH receptor exon 3 retention or deletion on first-year growth response and final height in patients with severe GH deficiency. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, v. 91, n. 3, p. 1076-1080, . (00/14092-4)

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