Prader WilliAngelman Syndrome

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Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are characteristics of disorders resulting from genomic imprinting in which the phenotypic expression of the disorder depends on the parent from whom the genetic abnormality is inherited. Both syndromes involve structural or functional loss of expression of genes in the chromosome 15q11-q13 region, including deletions, uniparental disomy, and mutations in an imprinting center. Paternally inherited abnormalities result in PWS while maternally inherited abnormalities result in AS (Knoll et al., 1989; Ledbetter et al., 1981). PWS is characterized by developmental delay, hypotonia, and feeding problems in infancy followed by excessive and rapid weight gain resulting in severe obesity, cryptoorchidism, short stature, and mild MR. Behavioral characteristics include temper tantrums and ritualistic or obsessive-compulsive behavior (Clarke, Boer, Cheung, Sturney, & Webb, 1996; Dykens, Leckman, & Cassify, 1996; Webb et al., 2002). The frequency of PWS is approximately 1/15,000 live births. In contrast, AS is characterized by severe MR, microcephaly, hypermotoric behavior with hand-flapping, and jerky movements in association with outbursts of laughter, short attention span, hypopigmented skin and eyes, and seizures with onset under 3 years of age.

It appears that different genes are responsible for the two syndromes, all of them imprinted in the germ line. The 15q11-q13 region contains four paternally expressed genes whose loss of expression causes PWS;

small nuclear ribonucleoprotein-associated polypeptide N (Ozcelik et al., 1992), zinc finger protein (Mowery-Rushton, Driscoll, Nicholls, Locker, & Surti, 1996), a gene designated as imprinted in Prader-Willi (Wevrick, Kerns, & Francke, 1994) and two less well-characterized transcripts, PAR1 and PAR5 (Sutcliffe et al., 1994). The 15q11-q13 region also contains the gene for E6-AP ubiquitin-protein ligase 3A (UBE3A) which is biallelically expressed in somatic tissue but is imprinted with preferential maternal expression in the brain (Albrecht et al., 1997; Jiang, Tsai, Bressler, & Beaudet, 1998; Matsuura et al., 1997); mutations in UBE3A are found in a small subset of patients with AS.

The effects of imprinting are also seen in cases of uniparental disomy (UPD) where maternal UPD represents loss of paternally expressed genes and is associated with PWS, while paternal UPD represents loss of maternally expressed genes and is associated with AS. Seventy percent of cases in PWS are associated with a 4 Mb deletion in 15Q11-q13, an additional 27% display maternal uniparental disomy and 1-2% of cases are associated with mutations and deletions in the imprinting center (Sutcliffe et al., 1994). As in PSW, 70% of AS cases have maternal deletions in the 15q11-q13 region, 3-5% have paternal uniparental disomy, 7-9% have imprinting mutations, 2-4% have mutations in UBE3A, while in 10-20% of cases, the molecular defect is still unknown (Nicholls, 1993; Wagstaff et al., 1992).

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