Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints.
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.
Department of Genetics, Case Western Reserve University School of Medicine, and Center for Human Genetics, University Hospitals of Cleveland, Cleveland, OH 44106-4955, USA.
J M
JM
Amos-Landgraf
Y
Y
Ji
W
W
Gottlieb
T
T
Depinet
A E
AE
Wandstrat
S B
SB
Cassidy
D J
DJ
Driscoll
P K
PK
Rogan
S
S
Schwartz
R D
RD
Nicholls
D017204:Angelman Syndrome / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D019457:Chromosome Breakage / Q000235:genetics*; D002872:Chromosome Deletion; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D003001:Cloning, Molecular; D020451:Contig Mapping; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics; D020440:Gene Duplication; D005854:Germ Cells / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D006822:Hybrid Cells; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008969:Molecular Sequence Data; D005810:Multigene Family; D011218:Prader-Willi Syndrome / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases
D020662:Guanine Nucleotide Exchange Factors; D012333:RNA, Messenger; C118566:HERC2 protein, human; D044767:Ubiquitin-Protein Ligases; D019204:GTP-Binding Proteins