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 PUGLIESE-PIRES, Patricia N. FMUSP-HC
FORTIN, Jean-Philippe
KOPIN, Alan S.
JORGE, Alexander A. L. FMUSP-HC 2011
dc.identifier.citation EUROPEAN JOURNAL OF ENDOCRINOLOGY, v.165, n.2, p.233-241, 2011
dc.identifier.issn 0804-4643
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.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 LIM/25 LIM/42
dc.identifier.doi 10.1530/EJE-11-0168
dc.identifier.pmid 21646290
dc.type.category original article
dc.type.version publishedVersion PUGLIESE-PIRES, Patricia N.:FM: ARTHUR, Thais:FM: LATRONICO, Ana Claudia:FM:MCM MENDONCA, Berenice B.:FM:MCM VILLARES, Sandra Mara F.:HC:ICHC JORGE, Alexander A. L.:FM:MCM · 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 WOS:000292727400007 2-s2.0-79960185154 BRISTOL ENGLAND
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dc.description.index MEDLINE
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hcfmusp.citation.wos 27 Brasil Estados Unidos

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