Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number

Medical Microbiology and Immunology, School of Medicine, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA.
Journal of Medical Genetics (Impact Factor: 5.64). 11/2008; 46(2):86-93. DOI: 10.1136/jmg.2008.061580
Source: PubMed

ABSTRACT Chromosome 15q11-13 contains a cluster of imprinted genes essential for normal mammalian neurodevelopment. Deficiencies in paternal or maternal 15q11-13 alleles result in Prader-Willi or Angelman syndromes, respectively, and maternal duplications lead to a distinct condition that often includes autism. Overexpression of maternally expressed imprinted genes is predicted to cause 15q11-13-associated autism, but a link between gene dosage and expression has not been experimentally determined in brain.
Postmortem brain tissue was obtained from a male with 15q11-13 hexasomy and a female with 15q11-13 tetrasomy. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used to measure 10 15q11-13 transcripts in maternal 15q11-13 duplication, Prader-Willi syndrome, and control brain samples. Southern blot, bisulfite sequencing and fluorescence in situ hybridisation were used to investigate epigenetic mechanisms of gene regulation.
Gene expression and DNA methylation correlated with parental gene dosage in the male 15q11-13 duplication sample with severe cognitive impairment and seizures. Strikingly, the female with autism and milder Prader-Willi-like characteristics demonstrated unexpected deficiencies in the paternally expressed transcripts SNRPN, NDN, HBII85, and HBII52 and unchanged levels of maternally expressed UBE3A compared to controls. Paternal expression abnormalities in the female duplication sample were consistent with elevated DNA methylation of the 15q11-13 imprinting control region (ICR). Expression of non-imprinted 15q11-13 GABA receptor subunit genes was significantly reduced specifically in the female 15q11-13 duplication brain without detectable GABRB3 methylation differences.
Our findings suggest that genetic copy number changes combined with additional genetic or environmental influences on epigenetic mechanisms impact outcome and clinical heterogeneity of 15q11-13 duplication syndromes.

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Available from: Janine M Lasalle, Jul 29, 2015
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    • "Mutations in GABA A receptor subunits genes have been associated to ASD. The chromosome 15q11, containing the genes coding the three GABA A receptor subunits α5, β3 and γ3 (GABRA5, GABRB3 and GABRG3, respectively) has been linked to ASD, and SNPs in the above mentioned genes have been associated to ASD (Buxbaum et al., 2002; Hogart et al., 2007, 2009). It is interesting to note that, among these genes, GABRB3 has also been indicated as susceptibility gene for childhood absence epilepsy (Urak et al., 2006). "
    Autism - A Neurodevelopmental Journey from Genes to Behaviour, 08/2011; , ISBN: 978-953-307-493-1
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    • "This may cause difference between maternal and paternal duplication animals as well and should be investigated. At the very least, there is a significant variability and diversity of clinical phenotypes and gene expression in human chromosome 15q11–q13 duplication syndrome (Hogart et al. 2009; Piard et al. 2010). Further detailed epigenetic analyses both in humans and mice will provide an insight into the imprinting mechanisms. "
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    ABSTRACT: Autism is a neurodevelopmental disorder that manifests in childhood as social behavioral abnormalities, such as abnormal social interaction, impaired communication, and restricted interest or behavior. Of the known causes of autism, duplication of human chromosome 15q11-q13 is the most frequently associated cytogenetic abnormality. Chromosome 15q11-q13 is also known to include imprinting genes. In terms of neuroscience, it contains interesting genes such as Necdin, Ube3a, and a cluster of GABA(A) subunits as well as huge clusters of non-coding RNAs (small nucleolar RNAs, snoRNAs). Phenotypic analyses of mice genetically or chromosomally engineered for each gene or their clusters on a region of mouse chromosome seven syntenic to human 15q11-q13 indicate that this region may be involved in social behavior, serotonin metabolism, and weight control. Further studies using these models will provide important clues to the pathophysiology of autism. This review overviews phenotypes of mouse models of genes in 15q11-q13 and their relationships to autism.
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    • "Overexpression of maternally imprinted genes through duplications of chromosome 15q11-q14 also display parent-oforigin effects, with maternal duplications being associated with a complex neurobehavioral phenotype that often includes autism, cognitive deficits, and seizures [Cook et al., 1997; Dawson et al., 2002; Wang et al., 2004; Vorstman et al., 2006; Hogart et al., 2009]. Conversely deletions of 15q14 lead to heart defects, cleft palate, and developmental delay (DD) [Erdogan et al., 2007]. "
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    ABSTRACT: The 15q11-q13 PWS/AS critical region involves genes that are characterized by genomic imprinting. Multiple repeat elements within the region mediate rearrangements, including interstitial duplications, interstitial triplications, and supernumerary isodicentric marker chromosomes, as well as the deletions that cause Prader-Willi syndrome (PWS) and Angelman syndrome (AS). Recently, duplications of maternal origin concerning the same critical region have been implicated in autism spectrum disorders (ASD). We present a 6-month-old girl carrying a de novo duplication of maternal origin of the 15q11.2-q14 PWS/AS region (17.73 Mb in size) [46,XX,dup(15)(q11.2-q14)] detected with a high-resolution microarray-based comparative genomic hybridization (array-CGH). The patient is characterized by severe hypotonia, obesity, microstomia, long eyelashes, hirsutism, microretrognathia, short nose, severe psychomotor retardation, and multiple episodes of drug-resistant epileptic seizures, while her brain magnetic resonance imaging (MRI) documented partial corpus callosum dysplasia. In our patient the duplicated region is quite large extending beyond the Prader-Willi-Angelman critical region (PWACR), containing a number of genes that have been shown to be involved in ASD, exhibiting a severe phenotype, beyond the typical PWS/AS clinical manifestations. Reporting of similar well-characterized clinical cases with clearly delineated breakpoints of the duplicated region will clarify the contribution of specific genes to the phenotype.
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