Abstract
BackgroundSilver-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.ResultsThe 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.ConclusionsWe 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.
Highlights
Silver-Russell syndrome (SRS) is characterized by severe intrauterine and postnatal growth failure and frequent body asymmetry
imprinting center region 1 (ICR1) hypomethylation in various tissues and in both body halves For the comparison of the degree and the characteristics of ICR1 hypomethylation in different tissues we examined blood leukocytes, cells from the oral mucosa and cultured fibroblasts
ICR1 hypomethylation was most severe in blood leukocytes, less severe in oral mucosa cells, and least severe in cultured skin fibroblasts
Summary
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. Silver-Russell syndrome (SRS; OMIM 180860) is a sporadically occurring, genetically and clinically heterogeneous 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. In SRS, hypomethylation of the paternal allele of the telomeric imprinting center region 1 (ICR1, named H19DMR) within the IGF2/H19 locus on 11p15 can be found in approximately 50% of the patients [8]. Maternal uniparental disomy of chromosome 7 is present in roughly 10% of SRS cases [14]; the remaining cases are of unknown etiology
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