title: Dosage-sensitivity of imprinted genes expressed in the brain: 15q11-q13 and neuropsychiatric illness.
abstract: Imprinted genes, those genes subject to parent-of-origin-specific epigenetic marking resulting in monoallelic parent-specific expression, are sensitive to subtle changes in expression dosage. This has been illustrated in a number of experimental models and the fact that both decreased (or complete loss) and increased imprinted gene expression can lead to human diseases. In the present paper, we discuss the consequence of increased dosage of imprinted genes for brain function, focusing on the PWS (Prader-Willi syndrome) locus on human chromosome 15q11-q13 and how predicted increases in dosage of maternally expressed imprinted genes from this interval are associated with a higher risk of developing psychotic illness. The evidence for this comes from individuals with PWS itself and also non-syndromic cases of psychosis in carriers of a maternally derived copy number variant spanning this locus. Of the known imprinted genes in this region, the prime candidate is maternally expressed UBE3A, which encodes E6-AP (E6-associated protein) ubiquitin ligase and has an influence on a number of important neurotransmitter systems. Furthermore, these findings point to the fact that brain function is exquisitely sensitive to both decreases and increases in the expression of imprinted genes.
authors.affiliation: Behavioural Genetics Group, Neuroscience and Mental Health Research Institute, Schools of Medicine and Psychology, Cardiff University, Cardiff CF14 4XN, U.K.
authors.forename: Gráinne I
authors.initials: GI
authors.lastname: McNamara
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Isles
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics*; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics / Q000502:physiology; D018628:Gene Dosage / Q000235:genetics / Q000502:physiology*; D018392:Genomic Imprinting / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D011218:Prader-Willi Syndrome / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000523:psychology; D023121:RNA, Messenger, Stored / Q000235:genetics; D012640:Seizures / Q000235:genetics*
chemical_list: D023121:RNA, Messenger, Stored