A human imprinting centre demonstrates conserved acquisition but diverged maintenance of imprinting in a mouse model for Angelman syndrome imprinting defects

Hum Mol Genet. 2006 Feb 1;15(3):393-404. doi: 10.1093/hmg/ddi456. Epub 2005 Dec 20.


Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are caused by the loss of imprinted gene expression from chromosome 15q11-q13. Imprinted gene expression in the region is regulated by a bipartite imprinting centre (IC), comprising the PWS-IC and the AS-IC. The PWS-IC is a positive regulatory element required for bidirectional activation of a number of paternally expressed genes. The function of the AS-IC appears to be to suppress PWS-IC function on the maternal chromosome through a methylation imprint acquired during female gametogenesis. Here we have placed the entire mouse locus under the control of a human PWS-IC by targeted replacement of the mouse PWS-IC with the equivalent human region. Paternal inheritance of the human PWS-IC demonstrates for the first time that a positive regulatory element in the PWS-IC has diverged. These mice show postnatal lethality and growth deficiency, phenotypes not previously attributed directly to the affected genes. Following maternal inheritance, the human PWS-IC is able to acquire a methylation imprint in mouse oocytes, suggesting that acquisition of the methylation imprint is conserved. However, the imprint is lost in somatic cells, showing that maintenance has diverged. This maternal imprinting defect results in expression of maternal Ube3a-as and repression of Ube3a in cis, providing evidence that Ube3a is regulated by its antisense and creating the first reported mouse model for AS imprinting defects.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angelman Syndrome / genetics*
  • Animals
  • Autoantigens
  • Conserved Sequence
  • DNA Methylation
  • Disease Models, Animal
  • Gene Expression Regulation
  • Gene Silencing
  • Genomic Imprinting / genetics*
  • Humans
  • Infant, Newborn / growth & development
  • Inheritance Patterns
  • Mice
  • Mice, Inbred C57BL
  • Obesity / genetics
  • Phenotype
  • Prader-Willi Syndrome / genetics
  • Promoter Regions, Genetic / genetics
  • Ribonucleoproteins, Small Nuclear / genetics
  • Ubiquitin-Protein Ligases / genetics
  • snRNP Core Proteins


  • Autoantigens
  • Ribonucleoproteins, Small Nuclear
  • snRNP Core Proteins
  • UBE3A protein, human
  • Ubiquitin-Protein Ligases