Somatic recombination rather than uniparental disomy suggested as another mechanism by which genetic imprinting may play a role in the etiology of Prader-Willi syndrome

Abstract

Six Prader-Willi syndrome (PWS) patients with normal karyotypes and their parents were analyzed to determine the nature of the molecular aberrations present in the proximal region of 15q and to determine the parental origin of the aberrant chromosome 15. In addition, the likelihood that uniparental disomy plays a significant role in the etiology of PWS patients with normal karyotypes was studied. Restriction fragment length polymorphisms (RFLPs) recognized by seven probes [pML34 (D15S9), pTD3-21, pCGS0.9, pCGS1.1 (D15S10), IR4.3 (D15S11), IR10.1 (DS15S12), p189-1 (D15S13), IR39 (D15S18), and CMW-1 (D15S24)] mapping to the Prader-Willi chromosome region (PWCR) and an additional two probes [pMS1-14 (D15S1); the cDNA of neuromedin B] mapping elsewhere on chromosome 15 were analyzed in the six PWS patients and their parents. Copy number of each locus within the PWCR was determined by densitometry. Molecular rearrangements of the proximal region of 15q were observed in all of the six probands and the origin of the aberrant chromosome 15 when determined was consistently paternal in origin. While data obtained from our six patients does not support the mechanism of disomy, results obtained from three of the six patients show more complex rearrangements hypothesized to have resulted from somatic recombination. These rearrangements have resulted in acquired homozygosity and the lack of a paternal allele at various loci within the PWCR. The presence of only a maternal contribution at certain loci as the result of somatic recombination may be another mechanism by which genetic imprinting plays a role in the presentation of the PWS phenotype.

A Narrow Segment of Maternal Uniparental Disomy of Chromosome 7q31-qter in Silver-Russell Syndrome Delimits a Candidate Gene Region

“…A pattern of mosaicism was not indicated by the results of blood DNA analysis, but it cannot be ruled out in other tissues. Somatic recombination has been suggested as a cause of segmental UPD for patUPD6q24-qter (Das et al 2000), patUPD11p15 in BWS (Henry et al 1993), matUPD14q23-q24.2 (Martin et al 1999, and in PWS (Nicholls et al 1989;Gregory et al 1991). Other explanations for the observed segmental matUPD7 are more complex.…”

Sister chromatid exchange in families with Angelman or Prader‐Willi syndrome

“…Although estimation of SCE provides a useful method of studying chromosome damage and repair, susceptibility to deletion will also depend upon chromatin structure and there may be a specific instability associated with the 15qllq13 region which predisposes to the deletion of chromatin without an increase in the actual number of chromosome breaks. Such mechanisms could include stretches of repetitive DNA (Donlon et al 1986) or a tendency to recombination which results in acquired homozygosity without deletion (Gregory et al 1991).…”

Evidence of Somatic Pairing in an Adenocarcinoma of the Lung.

“…Radman and Kinsella (1980) were the first to point-out the significance of somatic recombination in the origin of homozygosity of a heterozygous allele. Gregory et al (1991) proposed a model explaining somatic recombination in their study of Prader-Willi syndrome and Woodage et al (1994) in Bloom syndrome. Faruqi et al (1994) on the basis of their studies on normal amniotic cells and blood, demonstrated not only mitotic pairing and chiasma formation but also provided the first objective proof of chromatid exchange and consequently validity to the alternate method of loss of heterozygosity rather than mutation in the etiology of cancers and other genetic diseases controlled by Mendelian inheritance of recessive alleles.…”