Given their association with these neurodevelopmental disorders, the imprinted genes in this interval have been the most studied in terms of their contribution to brain and behaviour. For instance, human genetic and animal model studies have demonstrated that loss of expression of the maternally expressed

Ibrutinib gene UBE3A is the key cause of AS [6]. Indeed, a novel therapeutic technique is centred on reactivation of the normally silent paternal copy of UBE3A using topoisomerase inhibitors which, in a mouse model of AS, rescues the gene expression loss [7]. In addition to loss of expression being important for brain function, over-expression of UBE3A is also thought to be a major contributing factor to the neuropsychiatric problems associated with maternal micro-duplications spanning the 15q11-q13 interval [8]. Similar efforts have been made to identify a ‘PWS gene’. However, here the

story is less clear-cut, with many more paternally expressed genes in the interval, loss of which probably contributes to the overall PWS phenotype (Figure 1). Nevertheless, recent attention has focused on two of these genes as being key. A number of clinical cases with unique but overlapping microdeletions at 15q11.2, leading to loss of the paternal copy of the SNORD116 small nucleolar (sno)RNAs, also displayed the same failure to thrive, hypotonia, and hyperphagia that is observed in PWS patients with larger deletions and maternal uniparental disomy 9•, 10, 11 and 12]. Lending support to the idea that SNORD116 Etoposide plays a central role in Selleck MEK inhibitor PWS, Snord116del knockout mice bear many characteristics reminiscent of the human PWS phenotype, including postnatal growth retardation and failure to thrive 13 and 14]. Abnormal adult behaviours include increased anxiety/fear, motor learning deficiency and an apparent failed satiety response [13]. Although thought to be involved in the regulation of alternative splicing via its interaction with long non-coding RNAs [15], the mechanism by which SNORD116 results in

these behavioural changes is not clear. Interestingly, very recent evidence has highlighted the importance of IPW, another non-coding RNA in the aetiology of PWS through its regulation of separate imprinted loci, the DLK1-DIO3 cluster [16]. IPW is also deleted in all the SNORD116 deletion clinical cases 9• and 16], and expression of Ipw is attenuated in neural precursor cells derived from Snord116del mice [17]. This suggests that the phenotype seen in both the clinical cases and animal model cannot be wholly ascribed to the action of SNORD116. The advent of next generation sequencing techniques has also pointed to MAGEL2 as a key contributor to PWS [18•]. Four patients were identified with point mutations in the MAGEL2 gene that, when paternally derived, leads to a truncated protein rendering individuals without a functional expressed copy of MAGEL2.