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Post-Receptor IGF-1 Insensitivity Restricted to the MAPK Pathway in a Silver-Russell Syndrome Patient with Hypomethylation at the Imprinting Control Region on Chromosome 11.
MedLine Citation:
PMID:  22170793     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Background: 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 IGF-1 insensitivity.Objective: To assess in vitro IGF-1 action in fibroblasts culture from a SRS patient with IGF-1 insensitivity.Methods: Cultures of fibroblasts from one SRS patient with ICR1 demethylation and controls were established. The SRS patient has severe pre and postnatal growth failure, elevated IGF-1 level and no clear improvement in growth rate during rhGH treatment. IGF-1 action was assessed by cell proliferation, AKT and p42/44-MAPK phosphorylation. Gene expression was determined by real-time PCR.Results: Despite normal IGF-1R, fibroblast proliferation induced by IGF-1 was 50% lower in SRS fibroblasts in comparison to controls. SRS fibroblasts presented similar AKT but 65% decreased p42/44-MAPK phosphorylation. Expression of IGFBP-3 was significantly increased in SRS fibroblasts; however, there was no improvement in proliferation rate or MAPK pathway activation with desIGF-1, an analogue with low affinity for IGFBPs that retains the ability to activate IGF-1R. A PCR-array analysis disclosed a defect in MAPK pathway characterized by an increase of DUSP4 and MEF2C genes expression in patient fibroblasts.Conclusion: A post-receptor IGF-1 insensitivity was characterized in one SRS patient with ICR1 hypomethylation. Albeit our study was based on unique severely affected patient, it raises an intriguing possibility to explain the post-natal growth impairment observed in SRS patients. Analyses of larger cohorts are needed to explore the role of MAPK-pathway defect mediated growth failure in SRS.
Authors:
Luciana Ribeiro Montenegro; Andrea Castro Leal; Debora Cabral Coutinho; Helena Panteliou Valassi; Mirian Yumie Nishi; Ivo Jp Arnhold; Berenice Bilharinho Mendonca; Alexander Augusto de Lima Jorge
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-12-14
Journal Detail:
Title:  European journal of endocrinology / European Federation of Endocrine Societies     Volume:  -     ISSN:  1479-683X     ISO Abbreviation:  -     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9423848     Medline TA:  Eur J Endocrinol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
L Montenegro, Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil.
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