Genetic imprinting suggested by maternal heterodisomy in non-deletion Prader-Willi syndrome

Abstract

Prader-Willi syndrome (PWS) is the most common form of dysmorphic genetic obesity associated with mental retardation. About 60% of cases have a cytological deletion of chromosome 15q11q13 (refs 2, 3). These deletions occur de novo exclusively on the paternal chromosome. By contrast, Angelman syndrome (AS) is a very different clinical disorder and is also associated with deletions of region 15q11q13 (refs 6-8), indistinguishable from those in PWS except that they occur de novo on the maternal chromosome. The parental origin of the affected chromosomes 15 in these disorders could, therefore, be a contributory factor in determining their clinical phenotypes. We have now used cloned DNA markers specific for the 15q11q13 subregion to determine the parental origin of chromosome 15 in PWS individuals not having cytogenetic deletions; these individuals account for almost all of the remaining 40% of PWS cases. Probands in two families displayed maternal uniparental disomy for chromosome 15q11q13. This is the first demonstration that maternal heterodisomy--the presence of two different chromosome 15s derived from the mother--can be associated with a human genetic disease. The absence of a paternal contribution of genes in region 15q11q13, as found in PWS deletion cases, rather than a mutation in a specific gene(s) in this region may result in expression of the clinical phenotype. Thus, we conclude that a gene or genes in region 15q11q13 must be inherited from each parent for normal human development.

Molecular karyotyping of human hepatocellular carcinoma using single-nucleotide polymorphism arrays

“…For example, several HCC samples analysed in the present study had UPD or UPT, which may be missed or recognized as gain regions by CGH, as both CGH and array-based CGH can only detect total copy changes (Hashimoto et al, 2004;Katoh et al, 2005;Patil et al, 2005). Uniparental disomy or UPT are exceptional derivations of a pair of offspring chromosomes from one parent only (Engel, 1980) and cause an increased risk of recessive disorders, such as Wiedemann-Beckwith (Henry et al, 1991), Prader-Willi (Nicholls et al, 1989) and Angelman syndromes (Malcolm et al, 1991) owing to reduction to homozygosity (Engel, 1993). Furthermore, UPD regions have been shown to contain genes responsible for carcinogenesis, which have been implicated in Wilms' tumor (Grundy et al, 1994), leukemia (Raghavan et al, 2005) and breast cancer (Murthy et al, 2002), but have never been described in HCC.…”

Detection of Imprinted Genes by Single-Cell Allele-Specific Gene Expression

“…For instance, some imprinted genes play a decisive role in growth control and developmental processes. 6 The disruption of these genes causes severe genetic syndromes including Prader-Willi syndrome (PWS [MIM: 176270]), Angelman syndrome (AS [MIM: 105830]), [7][8][9] Beckwith-Wiedemann syndrome (BWS [MIM: 130650]), [10][11][12] Silver-Russell syndrome (SRS [MIM: 180860]), 13,14 Temple syndrome (TS14 [MIM: 616222]), and Kagami-Ogata syndrome (KOS14 [MIM: 608149]). 15 In the early 1990s, Igf2 (paternally expressed) and H19 (maternally expressed) were the first two imprinted genes to be discovered in mice.…”

A fascination with chromosome rescue in uniparental disomy: Mendelian recessive outlaws and imprinting copyrights infringements

“…Just as had happened with the first clinical report of UPD7, the interest in the subject matter took another turn with the report of the first case of UPD as an imprinting disorder. 10 This initial observation was that connecting UPD15 mat to the PWS.…”