Imprinting genomico e disordini della crescita: difetti genetici e meccanismi molecolari

Both Beckwith-Wiedemann Syndrome (BWS) and Silver-Russell syndrome (SRS) are caused by dysregulation of imprinted genes. 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. The molecular defects of most BWS and SRS cases are also epigenetic. Their cause is largely unknown. Also undefined are risk of recurrence, relation with the genotype (DNA sequence) and a precise correlation with the clinical pehnotype. This project has contributed to: a) increase our understanding of the molecular mechanisms underlying maintainence of genomic imprinting and associated defects by investigating cellular models and patients; b) define the relationship between DNA sequence variants and epigenetic defects, also informing on recurrence risks in BWS and SRS; c) identify a number of new molecular defects and define correlations between mutations and clinical features for patients stratification, correct prognosis and management of life-threatening co-morbidities in BWS and SRS (e.g. childood cancer in BWS).