Chromosome 15q11–13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number
Open accessAbstract
Background: 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. Methods: 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. Results: 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. Conclusion: 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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Maternal duplications of the 15q11-13 locus lead to increased expression of UBE3A and epigenetic silencing of the paternal antisense transcript, UBE3A-ATS.
“Maternal duplications of the 15q11–13 locus lead to increased expression of UBE3A and epigenetic silencing of the paternal antisense transcript, UBE3A-ATS121–124.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [123]
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- Authors
- Hogart, A., Leung, K. N., Wang, N. J., Wu, D. J., Driscoll, J., Vallero, R. O., Schanen, N. C., & LaSalle, J. M.
- Affiliations
- University of California, Davis (US)
- University of Delaware (US)
- Alfred I. duPont Hospital for Children (US)
- Corresponding author
- LaSalle, J M
- ORCID
- Venue
- Journal of Medical Genetics
- Publisher
- BMJ
- Published
- 2008-10-03
- Volume
- 46
- Issue
- 2
- Pages
- 86-93
- ISSN
- 0022-2593 (ISSN-L)
- 1468-6244
- PMC
- PMC2634820
- OpenAlex
- W2124390364
- Cited by
- 199
- References
- 39
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 6 · 2021: 7 · 2020: 2 · 2019: 7 · 2018: 37 · 2017: 4 · 2016: 5 · 2015: 9 · 2014: 12 · 2013: 14 · 2012: 18
- FWCI
- 13.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Medical Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1c06rr012088-01)
- National Institute of Mental Health (R24MH068855, F31MH078377)
- National Center for Research Resources (P20RR020173, C06-RR012088, C06 RR-12088-01)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U19 HD 35470, U19HD035470, R01HD048799)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- genomic imprinting, DNA methylation, gene dosage, Prader-Willi syndrome, Angelman syndrome, autism spectrum disorder, UBE3A, SNRPN, NDN, GABRB3, GABA receptor subunits, imprinting control regions, brain gene expression, copy number variation, clinical heterogeneity
- MeSH terms
- Adolescent, Adult, Aneuploidy, Brain, Chromosomes, Human, Pair 15, Female, Humans, Male, Prader-Willi Syndrome, Syndrome, Gene Expression, Angelman Syndrome, Gene Dosage, DNA Methylation, Gene Duplication, Epigenesis, Genetic
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