Molecular characterization of two proximal deletion breakpoint regions in both Prader-Willi and Angelman syndrome patients.
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct mental retardation syndromes caused by paternal and maternal deficiencies, respectively, in chromosome 15q11-q13. Approximately 70% of these patients have a large deletion of approximately 4 Mb extending from D15S9 (ML34) through D15S12 (IR10). To further characterize the deletion breakpoints proximal to D15S9, three new polymorphic microsatellite markers were developed that showed observed heterozygosities of 60%-87%. D15S541 and D15S542 were isolated from YAC A124A3 containing the D15S18 (IR39) locus. D15S543 was isolated from a cosmid cloned from the proximal right end of YAC 254B5 containing the D15S9 (ML34) locus. Gene-centromere mapping of these markers, using a panel of ovarian teratomas of known meiotic origin, extended the genetic map of chromosome 15 by 2-3 cM toward the centromere. Analysis of the more proximal S541/S542 markers on 53 Prader-Willi and 33 Angelman deletion patients indicated two classes of patients: 44% (35/80) of the informative patients were deleted for these markers (class I), while 56% (45/80) were not deleted (class II), with no difference between PWS and AS. In contrast, D15S543 was deleted in all informative patients (13/48) or showed the presence of a single allele (in 35/48 patients), suggesting that this marker is deleted in the majority of PWS and AS cases. These results confirm the presence of two common proximal deletion breakpoint regions in both Prader-Willi and Angelman syndromes and are consistent with the same deletion mechanism being responsible for paternal and maternal deletions. One breakpoint region lies between D15S541/S542 and D15S543, with an additional breakpoint region being proximal to D15S541/S542.
Christian
S L
SL
Diagnostic Development Branch, National Institutes of Health, Bethesda, MD 20892-0940, USA.
Robinson
W P
WP
Huang
B
B
Mutirangura
A
A
Line
M R
MR
Nakao
M
M
Surti
U
U
Chakravarti
A
A
Ledbetter
D H
DH
D017204:Angelman Syndrome / Q000235:genetics*; D001483:Base Sequence; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D004276:DNA, Satellite / Q000032:analysis; D005260:Female; D005819:Genetic Markers; D006801:Humans; D008126:Lod Score; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011218:Prader-Willi Syndrome / Q000235:genetics*; D017384:Sequence Deletion; D013724:Teratoma / Q000235:genetics
D004276:DNA, Satellite; D005819:Genetic Markers