Post-receptor IGF1 insensitivity restricted to the MAPK pathway in a Silver-Russell syndrome patient with hypomethylation at the imprinting control region on chromosome 11

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorMONTENEGRO, Luciana R.
dc.contributor.authorLEAL, Andrea C.
dc.contributor.authorCOUTINHO, Debora C.
dc.contributor.authorVALASSI, Helena P. L.
dc.contributor.authorNISHI, Mirian Y.
dc.contributor.authorPARNHOLD, Ivo J.
dc.contributor.authorMENDONCA, Berenice B.
dc.contributor.authorJORGE, Alexander A. L.
dc.date.accessioned2013-07-30T14:41:42Z
dc.date.available2013-07-30T14:41:42Z
dc.date.issued2012
dc.description.abstractBackground: Hypomethylation of the paternal imprinting center region 1 (ICR1) is the most frequent molecular cause of Silver-Russell syndrome (SRS). Clinical evidence suggests that patients with this epimutation have mild IGF1 insensitivity. Objective: To assess in vitro IGF1 action in fibroblast culture from a patient with SRS and IGF1 insensitivity. Methods: Fibroblast cultures from one patient with SRS due to ICR1 demethylation and controls were established. The SRS patient has severe growth failure, elevated IGF1 level, and poor growth rate during human recombinant GH treatment. IGF1 action was assessed by cell proliferation, AKT, and p42/44-MAPK phosphorylation. Gene expression was determined by real-time PCR. Results: Despite normal IGF1R sequence and expression, fibroblast proliferation induced by IGF1 was 50% lower in SRS fibroblasts in comparison with controls. IGF1 and insulin promoted a p42/44-MAPK activation in SRS fibroblasts 40 and 36%, respectively, lower than that in control fibroblasts. On the other hand, p42/44-MAPK activation induced by EGF stimulation was only slightly reduced (75% in SRS fibroblasts in comparison with control), suggesting a general impairment in MAPK pathway with a greater impairment of the stimulation induced by insulin and IGF1 than by EGF. A PCR array analysis disclosed a defect in MAPK pathway characterized by an increase in DUSP4 and MEF2C gene expressions in patient fibroblasts. Conclusion: A post-receptor IGF1 insensitivity was characterized in one patient with SRS and ICR1 hypomethylation. Although based on one unique severely affected patient, these results raise an intriguing mechanism to explain the postnatal growth impairment observed in SRS patients that needs confirmation in larger cohorts.
dc.description.indexMEDLINE
dc.description.sponsorshipFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [08/57915-2, 05/04726-0, 05/50144-2]
dc.description.sponsorshipConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [142062/06-5, 301339/2008-9, 300938/06-3, 307951/06-5]
dc.identifier.citationEUROPEAN JOURNAL OF ENDOCRINOLOGY, v.166, n.3, p.543-550, 2012
dc.identifier.doi10.1530/EJE-11-0964
dc.identifier.issn0804-4643
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/414
dc.language.isoeng
dc.publisherBIOSCIENTIFICA LTD
dc.relation.ispartofEuropean Journal of Endocrinology
dc.rightsrestrictedAccess
dc.rights.holderCopyright BIOSCIENTIFICA LTD
dc.subject.other11p15
dc.subject.othermethylation
dc.subject.otherbinding
dc.subject.otherprotein
dc.subject.otherassay
dc.subject.wosEndocrinology & Metabolism
dc.titlePost-receptor IGF1 insensitivity restricted to the MAPK pathway in a Silver-Russell syndrome patient with hypomethylation at the imprinting control region on chromosome 11
dc.typearticle
dc.type.categoryoriginal article
dc.type.versionpublishedVersion
dspace.entity.typePublication
hcfmusp.author.externalCOUTINHO, Debora C.:Univ Sao Paulo, Lab Hormonios & Genet Mol LIM 42, Unidade Endocrinol Desenvolvimento, Disciplina Endocrinol,Hosp Clin,Fac Med, BR-01246903 Sao Paulo, Brazil
hcfmusp.citation.scopus6
hcfmusp.contributor.author-fmusphcLUCIANA RIBEIRO MONTENEGRO
hcfmusp.contributor.author-fmusphcANDREA DE CASTRO LEAL
hcfmusp.contributor.author-fmusphcHELENA PANTELIOU LIMA VALASSI
hcfmusp.contributor.author-fmusphcMIRIAN YUMIE NISHI
hcfmusp.contributor.author-fmusphcIVO JORGE PRADO ARNHOLD
hcfmusp.contributor.author-fmusphcBERENICE BILHARINHO DE MENDONCA
hcfmusp.contributor.author-fmusphcALEXANDER AUGUSTO DE LIMA JORGE
hcfmusp.description.beginpage543
hcfmusp.description.endpage550
hcfmusp.description.issue3
hcfmusp.description.volume166
hcfmusp.lim.ref2012
hcfmusp.origemWOS
hcfmusp.origem.pubmed22170793
hcfmusp.origem.scopus2-s2.0-84857952205
hcfmusp.origem.wosWOS:000302343200023
hcfmusp.publisher.cityBRISTOL
hcfmusp.publisher.countryENGLAND
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