Benjamin Tycko, Editor ing within the bicistronic SNURF-SNRPN gene and express all tested paternally expressed genes in 15q11-q13, implicating the disrupted locus in PWS. However, the translocations in 2 patients with atypical “PWS-like” phenotypes lay distal of SNURF-SNRPN but proximal to the IPW gene (Figure 1a), which may indicate a role for genes at or on the distal side of the translocation. A unifying hypothesis is that the translocations affect neuronal chromatin structure, disrupting the function of multiple genes within 15q11-q13 through some form of position effect. Whereas it is also possible that the germline imprinting process (see below) is affected, the imprint may already have been set before the chromosome rearrangement, and this hypothesis is not fully compatible with the expression and methylation data.

Several mouse models have recently been developed for PWS or AS. These include animals with UPD and strains that carry a 4-Mb deletion affecting the region of the mouse genome that corresponds to human 15q11-q13. Interestingly, the deletion model segregates mouse phenotypes that mimic both PWS and AS, depending on the inheritance of the mutation. In addition, an imprinting mutation, discussed below, causes features of PWS, and targeted mutations of the murine Ube3a gene have been used to study AS (reviewed in ref. 6). The AS models display a mild neurobehavioral phenotype, observable only on careful testing, whereas the PWS mouse models all fail to thrive and often die shortly after birth. Failure to thrive is also seen in infants with PWS, and recent