Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty

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dc.contributor Sistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.author PUGLIESE-PIRES, Patricia N. FMUSP-HC
FORTIN, Jean-Philippe
ARTHUR, Thais FMUSP-HC
LATRONICO, Ana Claudia FMUSP-HC
MENDONCA, Berenice B. FMUSP-HC
VILLARES, Sandra Mara F. FMUSP-HC
PARNHOLD, Ivo J.
KOPIN, Alan S.
JORGE, Alexander A. L. FMUSP-HC
dc.date.issued 2011
dc.identifier.citation EUROPEAN JOURNAL OF ENDOCRINOLOGY, v.165, n.2, p.233-241, 2011
dc.identifier.issn 0804-4643
dc.identifier.uri http://observatorio.fm.usp.br/handle/OPI/22624
dc.description.abstract Background: A limited number of mutations in the GH secretagogue receptor gene (GHSR) have been described in patients with short stature. Objective: To analyze GHSR in idiopathic short stature (ISS) children including a subgroup of constitutional delay of growth and puberty (CDGP) patients. Subjects and methods: The GHSR coding region was directly sequenced in 96 independent patients with ISS, 31 of them with CDGP, in 150 adults, and in 197 children with normal stature. The pharmacological consequences of GHSR non-synonymous variations were established using in vitro cell-based assays. Results: Five different heterozygous point variations in GHSR were identified (c.-6 G>C, c.251G>T (p.Ser84Ile), c.505G>A (p.Ala169Thr), c.545 T>C (p.Val182Ala), and c.1072G>A (p.Ala358Thr)), all in patients with CDGP. Neither these allelic variants nor any other mutations were found in 694 alleles from controls. Functional studies revealed that two of these variations (p.Ser84Ile and p. Val182Ala) result in a decrease in basal activity that was in part explained by a reduction in cell surface expression. The p.Ser84Ile mutation was also associated with a defect in ghrelin potency. These mutations were identified in two female patients with CDGP (at the age of 13 years, their height SDS were -2.4 and -2.3). Both patients had normal progression of puberty and reached normal adult height (height SDS of -0.7 and -1.4) without treatment. Conclusion: This is the first report of GHSR mutations in patients with CDGP. Our data raise the intriguing possibility that abnormalities in ghrelin receptor function may influence the phenotype of individuals with CDGP.
dc.description.sponsorship · Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP [09/00313-3]
· Conselho-Nacional de Desenvolvimento Cientifico e Tecnologico CNPq [143524/2008-9, 300982/2009-7, 301477/2009-4]
· Fonds de la Recherche en Sante du Quebec
· Canadian Institutes of Health Research
· National Institute of Diabetes and Digestive and Kidney Diseases [R01DK072497]
dc.language.iso eng
dc.publisher BIOSCIENTIFICA LTD
dc.relation.ispartof European Journal of Endocrinology
dc.rights restrictedAccess
dc.subject.other ghrelin-receptor; hypogonadotropic hypogonadism; missense mutations; hormone release; short stature; amino-acid; identification; variants; children; stimulation
dc.title Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty
dc.type article
dc.rights.holder Copyright BIOSCIENTIFICA LTD
dc.description.group LIM/25
dc.description.group LIM/42
dc.identifier.doi 10.1530/EJE-11-0168
dc.identifier.pmid 21646290
dc.type.category original article
dc.type.version publishedVersion
hcfmusp.author PUGLIESE-PIRES, Patricia N.:FM:
hcfmusp.author ARTHUR, Thais:FM:
hcfmusp.author LATRONICO, Ana Claudia:FM:MCM
hcfmusp.author MENDONCA, Berenice B.:FM:MCM
hcfmusp.author VILLARES, Sandra Mara F.:HC:ICHC
hcfmusp.author JORGE, Alexander A. L.:FM:MCM
hcfmusp.author.external · FORTIN, Jean-Philippe:Tufts Med Ctr, Mol Pharmacol Res Ctr, Mol Cardiol Res Inst, Boston, MA USA
· PARNHOLD, Ivo J.:Univ Sao Paulo FMUSP, Fac Med, Disciplina Endocrinol, Lab Hormonios Genet Mol LIM 42,Unidad Endocrinol, BR-05403000 Sao Paulo, Brazil
· KOPIN, Alan S.:Tufts Med Ctr, Mol Pharmacol Res Ctr, Mol Cardiol Res Inst, Boston, MA USA
hcfmusp.origem.id WOS:000292727400007
hcfmusp.origem.id 2-s2.0-79960185154
hcfmusp.publisher.city BRISTOL
hcfmusp.publisher.country ENGLAND
hcfmusp.relation.reference · Altshuler D, 2010, NATURE, V467, P1061, DOI 10.1038/nature09534
· Al-Fulaij MA, 2007, J PHARMACOL EXP THER, V321, P298, DOI 10.1124/jpet.106.116384
· Lanktree MB, 2011, AM J HUM GENET, V88, P6, DOI 10.1016/j.ajhg.2010.11.007
· Liu G, 2007, J PHARMACOL EXP THER, V322, P1036, DOI 10.1124/jpet.107.123141
· Oertel BG, 2009, J BIOL CHEM, V284, P6530, DOI 10.1074/jbc.M807030200
· Semple RK, 2005, J CLIN ENDOCR METAB, V90, P1849, DOI 10.1210/jc.2004-1418
· Howard AD, 1996, SCIENCE, V273, P974, DOI 10.1126/science.273.5277.974
· Chandrashekar V, 2004, BIOL REPROD, V71, P17, DOI 10.1095/biolreprod.103.027060
· Hearn MG, 2002, P NATL ACAD SCI USA, V99, P14554, DOI 10.1073/pnas.202498299
· Teles MG, 2010, EUR J ENDOCRINOL, V163, P29, DOI 10.1530/EJE-10-0012
· Wang HJ, 2004, J CLIN ENDOCR METAB, V89, P157, DOI 10.1210/jc.2003-031395
· Allen HL, 2010, NATURE, V467, P832, DOI 10.1038/nature09410
· Pantel J, 2009, J CLIN ENDOCR METAB, V94, P4334, DOI 10.1210/jc.2009-1327
· Garcia EA, 2009, EUR J ENDOCRINOL, V161, P307, DOI 10.1530/EJE-09-0122
· Cohen P, 2008, J CLIN ENDOCR METAB, V93, P4210, DOI 10.1210/jc.2008-0509
· Sun YX, 2004, P NATL ACAD SCI USA, V101, P4679, DOI 10.1073/pnas.0305930101
· Pugliese-Pires PN, 2010, EUR J ENDOCRINOL, V163, P349, DOI 10.1530/EJE-10-0272
· Yang J, 2008, CELL, V132, P387, DOI 10.1016/j.cell.2008.01.017
· Tommiska J, 2010, J CLIN ENDOCR METAB, V95, P3063, DOI 10.1210/jc.2009-2344
· Kojima M, 1999, NATURE, V402, P656, DOI 10.1038/45230
· Reese MG, 1997, J COMPUT BIOL, V4, P311, DOI 10.1089/cmb.1997.4.311
· TANNER JM, 1966, ARCH DIS CHILD, V41, P454
· Wit JM, 2008, GROWTH HORM IGF RES, V18, P89, DOI 10.1016/j.ghir.2007.11.004
· Gutierrez JA, 2008, P NATL ACAD SCI USA, V105, P6320, DOI 10.1073/pnas.0800708105
· Kaplowitz PB, 2008, PEDIATRICS, V121, pS208, DOI 10.1542/peds.2007-1813F
· Holst B, 2003, MOL ENDOCRINOL, V17, P2201, DOI 10.1210/me.2003-0069
· Inoue H, 2011, J CLIN ENDOCR METAB, V96, pE373, DOI 10.1210/jc.2010-1570
· Pantel J, 2006, J CLIN INVEST, V116, P760, DOI 10.1172/JCI25303
· BEINBORN M, 1993, NATURE, V362, P348, DOI 10.1038/362348a0
· Ramensky V, 2002, NUCLEIC ACIDS RES, V30, P3894, DOI 10.1093/nar/gkf493
· Fortin JP, 2010, J PHARMACOL EXP THER, V332, P274, DOI 10.1124/jpet.109.160531
· Sedlmeyer IL, 2002, J CLIN ENDOCR METAB, V87, P1613, DOI 10.1210/jc.87.4.1613
· Sedlmeyer IL, 2002, J CLIN ENDOCR METAB, V87, P5581, DOI 10.1210/jc.2002-020862
· Shuto Y, 2002, J CLIN INVEST, V109, P1429, DOI 10.1172/JCI200213300
· Banerjee I, 2006, EUR J ENDOCRINOL, V155, P121, DOI 10.1530/eje.1.02184
· Banerjee I, 2008, EUR J ENDOCRINOL, V158, P473, DOI 10.1530/EJE-07-0769
· Blaker M, 1998, MOL PHARMACOL, V54, P857
· Fofanova-Gambetti OV, 2010, J CLIN ENDOCR METAB, V95, P4184, DOI 10.1210/jc.2010-0489
· Holst Birgitte, 2006, J Clin Invest, V116, P637, DOI 10.1172/JCI27999
· Sedlmeyer IL, 2005, J CLIN ENDOCR METAB, V90, P1091, DOI 10.1210/jc.2004-0649
· SHAPIRO MB, 1987, NUCLEIC ACIDS RES, V15, P7155, DOI 10.1093/nar/15.17.7155
· Silva EGP, 2003, HORM RES, V59, P229, DOI 10.1159/000070222
· Wehkalampi K, 2008, J CLIN ENDOCR METAB, V93, P723, DOI 10.1210/jc.2007-1786
dc.description.index MEDLINE
hcfmusp.citation.scopus 36
hcfmusp.citation.wos 27
hcfmusp.affiliation.country Brasil
hcfmusp.affiliation.country Estados Unidos


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