DEFECTIVE GENOMIC IMPRINTING AS CAUSE OF CONGENITAL GROWTH DISORDERS

The Beckwith-Wiedemann Syndrome (BWS) is a disease characterised by somatic overgrowth, macroglossia, visceromegaly, abdominal wall defects and increased risk of developing pediatric cancer. The Silver-Russell syndrome (SRS) is a heterogeneous syndrome which is characterised by severe intrauterine and postnatal growth retardation and typical dysmorphic features. The molecular data available suggest that BWS and SRS are caused by dysregulation of genes located on chromosome 11p15.5 and characterised by genomic imprinting. Genomic imprinting is a mechanism causing the expression of a gene to depend on its origin from mother or father. This process is controlled by epigenetic modifications, that are heritable characteristics of a gene (such as DNA methylation) not coded by its nucleotide sequence. Epigenetic defects and altered expression of imprinted genes of opposite types have been involved in BWS and SRS. The aim of this research project is to identify novel molecular alterations and determine the developmental stages, causes and mechanisms by which imprinting errors arise in BWS, SRS and related growth disorders.