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.
Amos-Landgraf
J M
JM
Department of Genetics, Case Western Reserve University School of Medicine, and Center for Human Genetics, University Hospitals of Cleveland, Cleveland, OH 44106-4955, USA.
Ji
Y
Y
Gottlieb
W
W
Depinet
T
T
Wandstrat
A E
AE
Cassidy
S B
SB
Driscoll
D J
DJ
Rogan
P K
PK
Schwartz
S
S
Nicholls
R D
RD
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