Prader-Willi and Angelman Syndromes: Sister imprinted disorders

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are clinically disti nct complex disorders mapped to chromosome 15q11-q13. They both have charac teristic neurologic, developmental, and behavioral phenotypes plus other st ructural end functional abnormalities. However, the cognitive and neurologi c impairment is more severe in AS, including seizures and ataxia. The behav ioral and endocrine disorders are more severe in PWS, including obsessive-c ompulsive symptoms and hypothalamic insufficiency. Both disorders can resul t from microdeletion, uniparental disomy, or an imprinting center defect in 15q11-q13, although the abnormality is on the paternally derived chromosom e 15 for PWS and the maternally derived 15 for AS because of genomic imprin ting. Although the same gene may control imprinting for both disorders, the gene(s) causing their phenotypes differ. AS results from underexpression o f a single gene, UBE3A, which codes for E6-AP, a protein that functions to transfer small ubiquitin molecules to certain target proteins, to enable th eir degradation. The genes responsible for PWS are not determined, although several maternally imprinted genes in 15q11-q13 are known. The most likely candidate is SNRPN, which codes for a small nuclear ribonucleoprotein, a r ibosome-associated protein that controls gene splicing and thus synthesis o f critical proteins in the brain. Animal models exist for both disorders. T he genetic relationship between PWS and AS makes them unique and potentiall y highly instructive disorders that contribute substantially to the populat ion burden of cognitive impairment. (C) 2000 Wiley-Liss, Inc.