Human Molecular Genetics, Vol 6, 387-395, Copyright © 1997 by Oxford University Press
M Zeschnigk, B Schmitz, B Dittrich, K Buiting, B Horsthemke and W Doerfler
A deletion of 15q11-q13 and uniparental disomy 15 lead to Prader-
Labhart-Willi syndrome (PWS) or Angelman syndrome (AS) because this region
contains genes expressed exclusively from the paternal (PWS) or maternal
(AS) chromosome, respectively. DNA methylation plays a role in the control
of imprinted gene expression, but so far only a few 5'-CG- 3' dinucleotides
within the recognition sites of the methylation sensitive enzymes have been
studied. As part of a study on DNA methylation patterns in the human
genome, we have applied the bisulfite protocol of genomic sequencing to
study all 5'-CG-3' dinucleotides around exon 1 of SNRPN and at the D15S63
locus, which contains a start site for alternative SNRPN transcripts
possibly involved in imprint switching during gametogenesis. At least 17
PCR products derived from single chromosomes of normal individuals as well
as PWS and AS patients have been sequenced. We have found that cytosine
residues outside 5'-CG- 3' dinucleotides are always unmethylated. However,
> 96% of all of the 23 5'-CG-3' dinucleotides around SNRPN exon 1 are
methylated on the maternal chromosome and completely devoid of methylation
on the paternal chromosome. This finding is in contrast to the D15S63
locus, where only the two Cfol/Hhal sites are methylated on the maternal
chromosome at the same frequency as seen for the SNRPN segment. At the
other five 5'-CG-3' dinucleotides, differential methylation is less
pronounced, i.e. 45-70% on the maternal chromosome and 5-14% on the
paternal chromosome. The differences between SNRPN and D15S63 methylation
may reflect different biological functions of the alternative SNRPN
transcripts. The systematic investigation of 5'-CG-3' methylation patterns
as reported here will provide the basis for a PCR- based methylation test
to diagnose PWS and AS.
ARTICLES
Imprinted segments in the human genome: different DNA methylation patterns in the Prader-Willi/Angelman syndrome region as determined by the genomic sequencing method
Institute for Genetics, University of Cologne, Germany.
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