33 Two clinically distinct disorders, Prader-Willi

and Angelman syndromes (PWS and AS) , arise from abnormalities of a small region in 15ql l-ql3.34 These syndromes have characteristic and distinct neurobehavioral profiles: in AS the retardation is severe (very few affected individuals can talk) and there is ataxia, seizures, abnormal EEG, microcephaly, facial dysmorphism, Inhibitors,research,lifescience,medical hyperactivity and paroxysmal laughter. By contrast, in PWS, the MR may be only mild; there is a characteristic facial appearance and a specific behavioral abnormality, ie, hyperphagia resulting in severe obesity. Despite the phenotypic differences, the basic defect is the same in the Inhibitors,research,lifescience,medical two disorders: a failure of parent-of-origin-specific gene expression. If both copies of chromosome 15 derive

from the mother then the individual will have PWS; if both are from the father then the phenotype is AS. The basic defect is not simply a dosage effect; it turns out that about a find more quarter of cases of PWS are not due to a deletion Inhibitors,research,lifescience,medical but to the inheritance of two maternal copies of chromosome 15 (rather than the usual situation of one maternal and one paternal). Conversely, two paternal copies of chromosome 15 result in AS. The chromosomal region is said to bear a parent-of-origin imprint, of which the molecular signature is a difference in DNA methylation.35 Mutations in a ubiquitin protein ligase gene (UBE3A) have been found in a few rare families with AS.36 The gene product is

part of a widely used ubiquitin-mediated protein Inhibitors,research,lifescience,medical degradation pathway. PWS is probably not the result of a defect in a single gene. Seven genes (and candidate genes) have been identified in the PWS region, all of Inhibitors,research,lifescience,medical which appear to be brain specific.29 It is not known if the phenotype is due to an abnormality in a single gene. However, there is now some evidence to suggest that abnormal RNA editing, due to misregulation of guide RNAs, mediates the defect in PWS. The nucleolus contains a large number of small RNAs, termed small nucleolar RNAs (snoRNAs); the majority of these snoRNAs function in the posttranscriptional modification of rRNA nucleotides. However, it is now clear that the action of methylation guide snoRNAs goes beyond the field of ribosome biogenesis. Recently three brain-specific snoRNAs, which are subject Terminal deoxynucleotidyl transferase to genomic imprinting in mice and humans, have been discovered within the 15qll critical region for PWS and AS.37 Unusually, they do not have appropriate antisense elements, so their function is not clear, but one has a similarity to the mRNA encoded by the gene for the serotonin receptor-2C. The sequence matches a conserved region subject to both alternative splicing and adenosine-to-inosine editing.