Molecular study of the Prader-Willi syndrome: deletion, RFLP, and phenotype analyses of 50 patients.
Deletion and RFLP studies with 5 cloned DNA markers localized at 15q11.2 were performed in 50 patients with the Prader-Willi syndrome (PWS). A one-copy density (deletion) for at least one of 4 loci, D15S9, D15S11, D15S10, D15S12, was detected in 32 (64%) of the 50 patients; deletions of each of the 4 loci were found in 29, 30, 29, and 28 patients, respectively. Three patients showed 4 or more copy density for D15S12 locus, in addition to deletions. The remaining 18 patients showed two-copy densities for each of the 4 loci. A common site of rearrangements among our 32 patients as well as the reported patients seemed to be confined to a segment between D15S9 and D15S11, suggesting the putative PWS gene locus in this segment. Of 6 patients who have cytologic deletions but did not show any molecular deletions, 3 have normal size of hands and feet, and 4 have normally pigmented skin and hair. The normal pigmentation was also observed in 3 patients who had small molecular deletions in the examined 5-locus segment. These observations may support the conception of contiguous gene syndrome. RFLP analysis demonstrated maternal uniparental isodisomy of chromosomes 15 in both a patient with 45,t(15q;15q) and a karyotypically normal patient. Based on the results of the present study, a new model is proposed to explain the occurrence of PWS with a variety of chromosome abnormalities, including partial monosomy, disomy, trisomy, and/or tetrasomy for 15q11.2. The normal development may require an even or more "number ratio" of paternally derived allele(s) to maternally derived allele(s) of the gene(s) localized at 15q11.2, and a disturbance of the ratio would lead to the PWS phenotype.
Hamabe
J
J
Department of Human Genetics, Nagasaki University School of Medicine, Japan.
Fukushima
Y
Y
Harada
N
N
Abe
K
K
Matsuo
N
N
Nagai
T
T
Yoshioka
A
A
Tonoki
H
H
Tsukino
R
R
Niikawa
N
N
D000293:Adolescent; D000328:Adult; D015139:Blotting, Southern; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D011218:Prader-Willi Syndrome / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics