Genetic Imprinting: The Paradigm of Prader-Willi and Angelman Syndromes

Imprinted genes are expressed from only one of the two parental alleles. A consequence of genomic imprinting is that viable embryos must receive two haploid genome complements from parents of opposite sex. The parental-specific expression is obtained through epigenetic modifications (DNA methylation, histone tail modifications) which alter the conformation of chromatin fiber and there-fore regulate the expression of the underlying genes. Deletions, duplication, mutations or alterations of imprinting of the only active allele, as well as uniparental disomy or loss of imprinting of the inactive allele lead to an unbalance (loss of function or gain of function) in the dosage of the gene product and may have phenotypic consequences. Two such examples in human pathology are rep-resented by the Prader-Willi and Angelman syndromes, whose phenotypes result from loss of paternal or maternal contribution of the 15 q11-q13 genomic region, respectively. Prader-Willi syndrome is characterized by pre- and postnatal hypotonia, feeding difficulties in early life and subsequent hyperphagia with obsessive/compulsive food searching, obesity, short stature, hypogonadism and acromicria. Psychomotor development is mildly affected and behavioral problems are more relevant. Patients with Angelman syndrome show a completely different phenotype characterized by severe mental retardation, absent speech, autistic-like behavior, severe epilepsy and postnatal microcephaly.