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Opposite (epi)mutations affecting the imprinted region 11p15 are associated with Silver-Russell (SRS) and Beckwith-Wiedemann syndrome (BWS). Apart from other disturbances more than 35% of patients with SRS show hypomethylation at the imprinting control region 1 (ICR1) in 11p15. ICR1 is paternally methylated and regulates the expression of the paternally expressed growth factor IGF2 and the maternally expressed gene H19. The exact function of the non-coding RNA H19 is still unknown. However, the finding that this gene is highly conserved in mammals indicates profound functional relevance. Due to the supposed function of H19 in the regulation of the imprinted region 11p15 we searched for mutations in the transcribed sequence and the CTCF binding sites of H19 in 44 patients with SRS. In two cases different 3 base-pair (bp) deletions in exon 1 could be identified. A third patient carried a 39 bp duplication affecting exon 2 and intron 2. These three variants were not detected in 100 controls and 42 patients with isolated growth retardation. One of the patients carrying a mutation also showed hypomethylation at the ICR1 in 11p15. Splicing studies in HEK cells transfected with constructs carrying the three different variants revealed a deviation from the normal H19 splicing pattern in two of these individuals. However, analysis of lymphocytes of one of these two patients did not verify an altered expression pattern of H19. Nevertheless, our results indicate a relevant role of H19 in the aetiology of SRS: functional effects of these variants on chromatin restructuring of the ICR1, or altered function of H19 as a posttranslational modifying factor (microRNA/antisense RNA) are conceivable.

Are H19 Variants Associated with Silver-Russell Syndrome?