Imprinting Establishment and Maintenance in the Prader-Willi/Angelman Syndrome

Karin Buiting
Institute for Human Genetics; Universitatsklinikum Essen

The Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are neurogenetic disorders, which are caused by the loss of function of imprinted genes in 15q11-q13. The most frequent lesions are a deletion of the entire region or uniparental disomy. In a small group of patients, the disease is due to aberrant imprinting and gene silencing. Incorrect imprints can occur de novo without any mutation in the DNA sequence or as the result of a microdeletion affecting the imprinting center (IC), which controls the whole imprinted domain. The IC maps to the SNURF-SNRPN locus and appears to consist of two elements. One element is required for the maintenance of the paternal imprint during early embryogenesis. The second element is required for maternal imprinting in the female germline.

Based on the detection of point mutations in some patients with AS, the UBE3A gene has been identified as the AS gene. In brain, UBE3A is expressed from the maternal allele only. There is tentative evidence that mono-allelic expression of this gene is regulated through a paternally-expressed antisense transcript, which starts at the IC. The SNURF-SNRPN sense UBE3A antisense transcript serves as a host for several snoRNAs, which are encoded within introns of this transcript. Unlike other snoRNAs, these snoRNAs are probably not involved in the posttranscriptional modification of rRNA, because they lack any telltale rRNA complementarity. Between SNURF-SNRPN and UBE3A the snoRNAs appear to be the only conserved entities between human and mouse. From the mouse data this region appears to be critical for the neonatal PWS phenotype and therefore a lack of these snoRNAs may be causally involved in this disease.