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Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome

Abstract

Silver-Russell syndrome (SRS, OMIM 180860) is a congenital disorder characterized by severe intrauterine and postnatal growth retardation, dysmorphic facial features and body asymmetry. SRS is genetically heterogenous with maternal uniparental disomy with respect to chromosome 7 occurring in 10% of affected individuals. Given the crucial role of the 11p15 imprinted region in the control of fetal growth, we hypothesized that dysregulation of genes at 11p15 might be involved in syndromic intrauterine growth retardation. We identified an epimutation (demethylation) in the telomeric imprinting center region ICR1 of the 11p15 region in several individuals with clinically typical SRS. This epigenetic defect is associated with, and probably responsible for, relaxation of imprinting and biallelic expression of H19 and downregulation of IGF2. These findings provide new insight into the pathogenesis of SRS and strongly suggest that the 11p15 imprinted region, in addition to those of 7p11.2-p13 and 7q31-qter, is involved in SRS.

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Figure 1: Methylation analysis of KCNQ1OT1 and H19 in individuals with SRS.
Figure 2: Methylation analysis of H19-IGF2 ICR1 in individuals with SRS.
Figure 3: Methylation and expression analyses of IGF2 in individuals with SRS.
Figure 4: Analysis of parental expression of H19 in blood cells from individual 6, her twin, her parents and a control subject.

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Acknowledgements

We thank A. Munnich for providing skin fibroblasts from a control subject and J.-P. Siffroi for culture fibroblasts from individuals with SRS. This work was supported by Pharmacia-Pfizer and Pierre Chatelain, INSERM U515, Université Pierre et Marie Curie and Assistance Publique Hôpitaux de Paris. S.R. was a recipient of NovoNordisk France.

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Correspondence to Christine Gicquel.

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Supplementary information

Supplementary Table 1

Clinical and molecular characteristics of patients with Silver-Russell syndrome. (PDF 58 kb)

Supplementary Table 2

Primer sequences. (PDF 40 kb)

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Gicquel, C., Rossignol, S., Cabrol, S. et al. Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet 37, 1003–1007 (2005). https://doi.org/10.1038/ng1629

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