Genetic Imprinting in the Prader–Willi and Angelman Syndromes

Abstract

Abstract Imprinted genes are expressed from only one of the two parental alleles: they are located in a few, specific chromosomal regions. The parental‐specific expression is obtained through epigenetic modifications (DNA methylation, histone tail modifications) which alter the conformation of chromatin fibre and therefore regulate the expression of the underlying genes. Deletions, duplications, mutations or imprinting defects 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 do have phenotypic consequences. Two such examples in human pathology are represented by the Prader–Willi and Angelman syndromes, two phenotypically different conditions, whose phenotypes result from loss of paternal or maternal contribution of the 15q11–q13 genomic region, respectively. Key Concepts: Prader–Willi and Angelman syndromes are caused by loss of function of different genes located in a genomic region under the control of a single, bipartite imprinting centre. These two condition represent the prototype of genomic imprinting disorders in humans. Genomic imprinting regulates allelic expression according to the parental origin. Imprinted genes are commonly expressed in half dosage. Imprinted genes can be inactivated by different mechanisms: uniparental disomy, microdeletion, gene mutation, primary or secondary epigenetic mutation of the imprinting centre.