Mechanisms of imprinting of the Prader-Willi/Angelman region.
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.
Horsthemke
Bernhard
B
Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany. bernhard.horsthemke@uni-due.de
Wagstaff
Joseph
J
D017204:Angelman Syndrome / Q000235:genetics*; D000818:Animals; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D018392:Genomic Imprinting; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D011218:Prader-Willi Syndrome / Q000235:genetics*; D016372:RNA, Antisense / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D016372:RNA, Antisense; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases