The contribution of imprinted genes to neurodevelopmental and neuropsychiatric disorders

Abstract

Imprinted genes are a subset of mammalian genes that are subject to germline parent-specific epigenetic modifications leading monoallelic expression. Imprinted gene expression is particularly prevalent in the brain and it is unsurprising that mutations affecting their expression can lead to neurodevelopmental and/or neuropsychiatric disorders in humans. Here I review the evidence for this, detailing key neurodevelopmental disorders linked to imprinted gene clusters on human chromosomes 15q11-q13 and 14q32, highlighting genes and possible regulatory links between these different syndromes. Similarly, rare copy number variant mutations at imprinted clusters also provide strong links between abnormal imprinted gene expression and the predisposition to severe psychiatric illness. In addition to direct links between brain-expressed imprinted genes and neurodevelopmental and/or neuropsychiatric disorders, I outline how imprinted genes that are expressed in another tissue hotspot, the placenta, contribute indirectly to abnormal brain and behaviour. Specifically, altered nutrient provisioning or endocrine signalling by the placenta caused by abnormal expression of imprinted genes may lead to increased prevalence of neurodevelopmental and/or neuropsychiatric problems in both the offspring and the mother.

Fig. 1. Schematic showing the imprinted gene clusters on human chromosomes 14q32 and 15q11-q13.

Paternally expressed imprinted genes are represented in blue, maternally imprinted genes in red, biallelic genes in black; DNA-me is represented by “lollipops” and these define the associated DMRs (direction indicates whether methylated on paternal or maternal chromosome). Both imprinted clusters contain maternally and paternally expressed protein coding genes, snoRNA species and non-coding and/or micro-RNA molecules. The schematic also shows how the non-coding RNA IPW transcribed from the paternal chromosome 15 is linked to the imprinting on chromosome 14. Specifically, IPW is thought to link with the histone methyltransferase G9A, bind to the DMR and suppress gene expression on the paternal chromosome 14, thus leading to maternal only expression of MEG3, MEG8, the SNORD112-4 and MIR clusters.

Fig. 2. Family tree depicting transmission of 15q11-q13 duplications and neuropsychiatric phenotypes.

Red fill indicates maternal duplications, blue indicates paternal duplications, and grey indicates no duplications. Samples where no DNA was available have no fill. Neuropsychiatric phenotype is indicated as follows: SZ schizophrenia, UA unaffected. In this particular pedigree the mother has inherited the duplication paternally and is (in this case) unaffected. However, when the duplication is passed through her germline the imprint is then reset and the CNV is inherited maternally in her offspring, leading to schizophrenia. Figure adapted from Isles et al. [61].