Mechanisms and brain specific consequences of genomic imprinting in Prader-Willi and Angelman syndromes

Genomic imprinting is a curious manifestation of epigenetic inheritance that defies normal Mendelian genetics. Most vertebrate genes are expressed from both, the paternal and maternal alleles. However, a subset of mammalian genes is monoallelically expressed in a parent-of-origin manner due to imprinting mechanisms that confer a parent-specific memory to individual cells. Epigenetically correct inheritance of imprinted genes requires appropriate germ-line specific chromosomal modifications like histone acetylation or DNA methylation. Some of these modified, imprinted genes are organized in clusters as exemplified by the 2 Mb domain on human chromosome 15q11-q13. Deletion, uniparental disomy (UPD), or inappropriate imprinting of this chromosomal region results in the neurogenetic disorders Prader-Willi syndrome (PWS) and Angelman syndrome (AS), respectively. Recently, new genes and regulatory mechanisms that contribute to imprint regulation within the affected regions have been characterized. This review focuses on the role of these imprinted genes on human chromosome 15q11-13, imprinting center elements, and epigenetic mechanisms in the development of specific regions of the mammalian brain.