Mechanisms of imprinting of the Prader-Willi/Angelman region

Abstract

Prader–Willi syndrome (PWS) and Angelman syndrome (AS) are two distinct neurodevelopmental disorders, each caused by several genetic and epigenetic mechanisms involving the proximal long arm of chromosome 15. Lack of a functional paternal copy of 15q11–q13 causes PWS; lack of a functional maternal copy of UBE3A, a gene within 15q11–q13, causes AS. This region of chromosome 15 contains a number of imprinted genes that are coordinately regulated by an imprinting center (PWS/AS‐IC) that contains two functional elements, the PWS‐SRO and the AS‐SRO. A chromosome lacking the PWS‐SRO has the maternal state of gene activity and epigenetic modification after either maternal or paternal transmission; a chromosome lacking the AS‐SRO but containing the PWS‐SRO has the paternal state of gene activity and epigenetic modification after either maternal or paternal transmission. The maternal state of chromosome 15q11–q13 is associated with methylation of the PWS‐SRO, while the paternal state is associated with lack of methylation of the PWS‐SRO. Although most models of PWS/AS region imprinting assume that the PWS‐SRO is methylated during oogenesis and that this methylation of the maternal PWS‐SRO is maintained after fertilization, several lines of evidence suggest that the maternal PWS‐SRO is in fact not methylated until after fertilization. Imprinting defects affecting the PWS/AS region can arise from failure to demethylate the PWS‐SRO in the male germ line, from failure to methylate the maternal PWS‐SRO, or from failure to maintain PWS‐SRO methylation after fertilization. © 2008 Wiley‐Liss, Inc.