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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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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Author(s):
Montenegro, Luciana R. [1] ; Leal, Andrea C. [1] ; Coutinho, Debora C. [1] ; Valassi, Helena P. L. [1] ; Nishi, Mirian Y. [1] ; PArnhold, Ivo J. [1] ; Mendonca, Berenice B. [1] ; Jorge, Alexander A. L. [2]
Total Authors: 8
Affiliation:
[1] Univ Sao Paulo, Lab Hormonios & Genet Mol LIM 42, Unidade Endocrinol Desenvolvimento, Disciplina Endocrinol, Hosp Clin, Fac Med, BR-01246903 Sao Paulo - Brazil
[2] Univ Sao Paulo, Lab Endocrinol Celular & Mol LIM 25, Unidade Endocrinologia Genet, Disciplina Endocrinol, Hosp Clin, Fac Med, Fac Med U, BR-01246903 Sao Paulo - Brazil
Total Affiliations: 2
Document type: Journal article
Source: EUROPEAN JOURNAL OF ENDOCRINOLOGY; v. 166, n. 3, p. 543-550, MAR 2012.
Web of Science Citations: 7
Abstract

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 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. (AU)

FAPESP's process: 05/04726-0 - Molecular characterization of congenital endocrine diseases that affect growth and development
Grantee:Ana Claudia Latronico Xavier
Support Opportunities: Research Projects - Thematic Grants