IGF2/H19 hypomethylation is tissue, cell, and CpG site dependent and not correlated with body asymmetry in adolescents with Silver-Russell syndrome

Kannenberg Kai, Weber Karin, Binder Cathrin, Urban Christina, Kirschner Hans-Joachim, Binder, Binder Gerhard

Description

Silver-Russell syndrome (SRS) is characterized by severe intrauterine and postnatal growth failure and frequent body asymmetry. Half of the patients with SRS carry a DNA hypomethylation of the imprinting center region 1 (ICR1) of the insulin-like growth factor 2 ( IGF2 )/ H19 locus, and the clinical phenotype is most severe in these patients. We aimed to elucidate the epigenetic basis of asymmetry in SRS and the cellular consequences of the ICR1 hypomethylation. Results The ICR1 methylation status was analyzed in blood and in addition in buccal smear probes and cultured fibroblasts obtained from punch biopsies taken from the two body halves of 5 SRS patients and 3 controls. We found that the ICR1 hypomethylation in SRS patients was stronger in blood leukocytes and oral mucosa cells than in fibroblasts. ICR1 CpG sites were affected differently. The severity of hypomethylation was not correlated to body asymmetry. IGF2 expression and IGF-II secretion of fibroblasts were not correlated to the degree of ICR1 hypomethylation. SRS fibroblasts responded well to stimulation by recombinant human IGF-I or IGF-II, with proliferation rates comparable with controls. Clonal expansion of primary fibroblasts confirmed the complexity of the cellular mosaicism. Conclusions We conclude that the ICR1 hypomethylation SRS is tissue, cell, and CpG site specific. The correlation of the ICR1 hypomethylation to IGF2 and H19 expression is not strict, may depend on the investigated tissue, and may become evident only in case of more severe methylation defects. The body asymmetry in juvenile SRS patients is not related to a corresponding ICR1 hypomethylation gradient, rendering more likely an intrauterine origin of asymmetry. Overall, it may be instrumental to consider not only the ICR1 methylation status as decisive for IGF2 / H19 expression regulation.

Sujets

• Silver?Russell syndrome
• DNA methylation
• Factor de crecimiento de tipo insulina tipo II

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 8
• Langue: English

Extrait

Kannenberget al. Clinical Epigenetics2012,4:15 http://www.clinicalepigeneticsjournal.com/content/4/1/15

R E S E A R C HOpen Access IGF2/H19hypomethylation is tissue, cell, and CpG site dependent and not correlated with body asymmetry in adolescents with SilverRussell syndrome 1* 11 12 1 Kai Kannenberg, Karin Weber , Cathrin Binder , Christina Urban , HansJoachim Kirschnerand Gerhard Binder

Abstract Background:SilverRussell syndrome (SRS) is characterized by severe intrauterine and postnatal growth failure and frequent body asymmetry. Half of the patients with SRS carry a DNA hypomethylation of the imprinting center region 1 (ICR1) of the insulinlike growth factor 2 (IGF2)/H19locus, and the clinical phenotype is most severe in these patients. We aimed to elucidate the epigenetic basis of asymmetry in SRS and the cellular consequences of the ICR1 hypomethylation. Results:The ICR1 methylation status was analyzed in blood and in addition in buccal smear probes and cultured fibroblasts obtained from punch biopsies taken from the two body halves of 5 SRS patients and 3 controls. We found that the ICR1 hypomethylation in SRS patients was stronger in blood leukocytes and oral mucosa cells than in fibroblasts. ICR1 CpG sites were affected differently. The severity of hypomethylation was not correlated to body asymmetry.IGF2expression and IGFII secretion of fibroblasts were not correlated to the degree of ICR1 hypomethylation. SRS fibroblasts responded well to stimulation by recombinant human IGFI or IGFII, with proliferation rates comparable with controls. Clonal expansion of primary fibroblasts confirmed the complexity of the cellular mosaicism. Conclusions:We conclude that the ICR1 hypomethylation SRS is tissue, cell, and CpG site specific. The correlation of the ICR1 hypomethylation toIGF2andH19expression is not strict, may depend on the investigated tissue, and may become evident only in case of more severe methylation defects. The body asymmetry in juvenile SRS patients is not related to a corresponding ICR1 hypomethylation gradient, rendering more likely an intrauterine origin of asymmetry. Overall, it may be instrumental to consider not only the ICR1 methylation status as decisive forIGF2/H19 expression regulation. Keywords:SilverRussell syndrome, DNA methylation, Body asymmetry, Skin fibroblast culture, IGFII

Background SilverRussell syndrome (SRS; OMIM 180860) is a spor adically occurring, genetically and clinically heteroge neous disorder. It is diagnosed on the basis of the combination of intrauterine growth retardation, severe short stature, characteristic triangular face, relative macrocephaly, body asymmetry, underweight, and

* Correspondence: [e-mail]tuebingen.de 1 University Children’s Hospital Tübingen Pediatric Endocrinology, 72076 Tübingen, Germany Full list of author information is available at the end of the article

several minor abnormalities [13]. The relative limb length differences in asymmetric SRS patients are present at birth and stay stable during the growth process [4]. Short stature in SRS can be treated with pharmacological doses of recombinant growth hormone [5]. There is no apparent hormone deficiency. In con trast, insulinlike growth factor (IGF)I and IGFII, and insulinlike growth factor binding protein 3 (IGFBP3) serum levels are frequently inappropriately high in rela tion to the short stature, suggesting some kind of IGFI insensitivity [6,7].

© 2012 Kannenberg et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.