Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints

Am J Hum Genet. 1999 Aug;65(2):370-86. doi: 10.1086/302510.


Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurobehavioral disorders that most often arise from a 4-Mb deletion of chromosome 15q11-q13 during paternal or maternal gametogenesis, respectively. At a de novo frequency of approximately.67-1/10,000 births, these deletions represent a common structural chromosome change in the human genome. To elucidate the mechanism underlying these events, we characterized the regions that contain two proximal breakpoint clusters and a distal cluster. Novel DNA sequences potentially associated with the breakpoints were positionally cloned from YACs within or near these regions. Analyses of rodent-human somatic-cell hybrids, YAC contigs, and FISH of normal or rearranged chromosomes 15 identified duplicated sequences (the END repeats) at or near the breakpoints. The END-repeat units are derived from large genomic duplications of a novel gene (HERC2), many copies of which are transcriptionally active in germline tissues. One of five PWS/AS patients analyzed to date has an identifiable, rearranged HERC2 transcript derived from the deletion event. We postulate that the END repeats flanking 15q11-q13 mediate homologous recombination resulting in deletion. Furthermore, we propose that active transcription of these repeats in male and female germ cells may facilitate the homologous recombination process.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angelman Syndrome / genetics*
  • Animals
  • Cell Line
  • Chromosome Breakage / genetics*
  • Chromosome Deletion
  • Chromosomes, Human, Pair 15 / genetics
  • Cloning, Molecular
  • Contig Mapping
  • Female
  • GTP-Binding Proteins / genetics
  • Gene Duplication
  • Germ Cells / metabolism
  • Guanine Nucleotide Exchange Factors*
  • Humans
  • Hybrid Cells
  • In Situ Hybridization, Fluorescence
  • Male
  • Molecular Sequence Data
  • Multigene Family
  • Prader-Willi Syndrome / genetics*
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Recombination, Genetic / genetics*
  • Repetitive Sequences, Nucleic Acid / genetics*
  • Transcription, Genetic / genetics*
  • Ubiquitin-Protein Ligases


  • Guanine Nucleotide Exchange Factors
  • RNA, Messenger
  • HERC2 protein, human
  • Ubiquitin-Protein Ligases
  • GTP-Binding Proteins

Associated data

  • GENBANK/AF140512
  • GENBANK/AF140513
  • GENBANK/AF140514
  • GENBANK/AF140515
  • GENBANK/AF140516
  • GENBANK/AF140517
  • GENBANK/AF140518
  • GENBANK/AF140519