Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Molecular Autism
Published in: Molecular Autism 1/2011

Open Access 01-12-2011 | Research

Increased copy number for methylated maternal 15q duplications leads to changes in gene and protein expression in human cortical samples

Authors: Haley A Scoles, Nora Urraca, Samuel W Chadwick, Lawrence T Reiter, Janine M LaSalle

Published in: Molecular Autism | Issue 1/2011

Login to get access

Abstract

Background

Duplication of chromosome 15q11-q13 (dup15q) accounts for approximately 3% of autism cases. Chromosome 15q11-q13 contains imprinted genes necessary for normal mammalian neurodevelopment controlled by a differentially methylated imprinting center (imprinting center of the Prader-Willi locus, PWS-IC). Maternal dup15q occurs as both interstitial duplications and isodicentric chromosome 15. Overexpression of the maternally expressed gene UBE3A is predicted to be the primary cause of the autistic features associated with dup15q. Previous analysis of two postmortem dup15q frontal cortical samples showed heterogeneity between the two cases, with one showing levels of the GABAA receptor genes, UBE3A and SNRPN in a manner not predicted by copy number or parental imprint.

Methods

Postmortem human brain tissue (Brodmann area 19, extrastriate visual cortex) was obtained from 8 dup15q, 10 idiopathic autism and 21 typical control tissue samples. Quantitative PCR was used to confirm duplication status. Quantitative RT-PCR and Western blot analyses were performed to measure 15q11-q13 transcript and protein levels, respectively. Methylation-sensitive high-resolution melting-curve analysis was performed on brain genomic DNA to identify the maternal:paternal ratio of methylation at PWS-IC.

Results

Dup15q brain samples showed a higher level of PWS-IC methylation than control or autism samples, indicating that dup15q was maternal in origin. UBE3A transcript and protein levels were significantly higher than control and autism in dup15q, as expected, although levels were variable and lower than expected based on copy number in some samples. In contrast, this increase in copy number did not result in consistently increased GABRB3 transcript or protein levels for dup15q samples. Furthermore, SNRPN was expected to be unchanged in expression in dup15q because it is expressed from the single unmethylated paternal allele, yet SNRPN levels were significantly reduced in dup15q samples compared to controls. PWS-IC methylation positively correlated with UBE3A and GABRB3 levels but negatively correlated with SNRPN levels. Idiopathic autism samples exhibited significantly lower GABRB3 and significantly more variable SNRPN levels compared to controls.

Conclusions

Although these results show that increased UBE3A/UBE3A is a consistent feature of dup15q syndrome, they also suggest that gene expression within 15q11-q13 is not based entirely on copy number but can be influenced by epigenetic mechanisms in brain.
Appendix
Available only for authorised users
Literature
1.
Prevalence of autism spectrum disorders - Autism and Developmental Disabilities Monitoring Network, United States, 2006. MMWR Surveill Summ. 2009, 58: 1-20.
2.
Bill BR, Geschwind DH: Genetic advances in autism: heterogeneity and convergence on shared pathways. Curr Opin Genet Dev. 2009, 19: 271-278. 10.1016/j.gde.2009.04.004.PubMedCentralCrossRefPubMed
3.
Bourgeron T: A synaptic trek to autism. Curr Opin Neurobiol. 2009, 19: 231-234. 10.1016/j.conb.2009.06.003.CrossRefPubMed
4.
Depienne C, Moreno-De-Luca D, Heron D, Bouteiller D, Gennetier A, Delorme R, Chaste P, Siffroi JP, Chantot-Bastaraud S, Benyahia B: Screening for Genomic Rearrangements and Methylation Abnormalities of the 15q11-q13 Region in Autism Spectrum Disorders. Biol Psychiatry. 2009
5.
Schroer RJ, Phelan MC, Michaelis RC, Crawford EC, Skinner SA, Cuccaro M, Simensen RJ, Bishop J, Skinner C, Fender D, Stevenson RE: Autism and maternally derived aberrations of chromosome 15q. Am J Med Genet. 1998, 76: 327-336. 10.1002/(SICI)1096-8628(19980401)76:4<327::AID-AJMG8>3.0.CO;2-M.CrossRefPubMed
6.
7.
Cook EH, Lindgren V, Leventhal BL, Courchesne R, Lincoln A, Shulman C, Lord C, Courchesne E: Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet. 1997, 60: 928-934.PubMedCentralPubMed
8.
Battaglia A: The inv dup(15) or idic(15) syndrome: a clinically recognisable neurogenetic disorder. Brain & development. 2005, 27: 365-369. 10.1016/j.braindev.2004.08.006.CrossRef
9.
Christian SL, Fantes JA, Mewborn SK, Huang B, Ledbetter DH: Large genomic duplicons map to sites of instability in the Prader-Willi/Angelman syndrome chromosome region (15q11-q13). Hum Mol Genet. 1999, 8: 1025-1037. 10.1093/hmg/8.6.1025.CrossRefPubMed
10.
Makoff AJ, Flomen RH: Detailed analysis of 15q11-q14 sequence corrects errors and gaps in the public access sequence to fully reveal large segmental duplications at breakpoints for Prader-Willi, Angelman, and inv dup(15) syndromes. Genome Biol. 2007, 8: R114-10.1186/gb-2007-8-6-r114.PubMedCentralCrossRefPubMed
11.
Sutcliffe JS, Nakao M, Christian S, Orstavik KH, Tommerup N, Ledbetter DH, Beaudet AL: Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nat Genet. 1994, 8: 52-58. 10.1038/ng0994-52.CrossRefPubMed
12.
Wahlstrom J, Steffenburg S, Hellgren L, Gillberg C: Chromosome findings in twins with early-onset autistic disorder. Am J Med Genet. 1989, 32: 19-21. 10.1002/ajmg.1320320105.CrossRefPubMed
13.
Milner KM, Craig EE, Thompson RJ, Veltman MW, Thomas NS, Roberts S, Bellamy M, Curran SR, Sporikou CM, Bolton PF: Prader-Willi syndrome: intellectual abilities and behavioural features by genetic subtype. J Child Psychol Psychiatry. 2005, 46: 1089-1096. 10.1111/j.1469-7610.2005.01520.x.CrossRefPubMed
14.
Veltman MW, Thompson RJ, Roberts SE, Thomas NS, Whittington J, Bolton PF: Prader-Willi syndrome--a study comparing deletion and uniparental disomy cases with reference to autism spectrum disorders. Eur Child Adolesc Psychiatry. 2004, 13: 42-50. 10.1007/s00787-004-0354-6.CrossRefPubMed
15.
Bolton PF, Dennis NR, Browne CE, Thomas NS, Veltman MW, Thompson RJ, Jacobs P: The phenotypic manifestations of interstitial duplications of proximal 15q with special reference to the autistic spectrum disorders. Am J Med Genet. 2001, 105: 675-685. 10.1002/ajmg.1551.CrossRefPubMed
16.
Rougeulle C, Glatt H, Lalande M: The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain [letter] [In Process Citation]. Nat Genet. 1997, 17: 14-15. 10.1038/ng0997-14.CrossRefPubMed
17.
Yamasaki K, Joh K, Ohta T, Masuzaki H, Ishimaru T, Mukai T, Niikawa N, Ogawa M, Wagstaff J, Kishino T: Neurons but not glial cells show reciprocal imprinting of sense and antisense transcripts of Ube3a. Hum Mol Genet. 2003, 12: 837-847. 10.1093/hmg/ddg106.CrossRefPubMed
18.
Kashiwagi A, Meguro M, Hoshiya H, Haruta M, Ishino F, Shibahara T, Oshimura M: Predominant maternal expression of the mouse Atp10c in hippocampus and olfactory bulb. J Hum Genet. 2003, 48: 194-198. 10.1007/s10038-003-0009-3.CrossRefPubMed
19.
Meguro M, Kashiwagi A, Mitsuya K, Nakao M, Kondo I, Saitoh S, Oshimura M: A novel maternally expressed gene, ATP10C, encodes a putative aminophospholipid translocase associated with Angelman syndrome. Nat Genet. 2001, 28: 19-20.PubMed
20.
DuBose AJ, Johnstone KA, Smith EY, Hallett RA, Resnick JL: Atp10a, a gene adjacent to the PWS/AS gene cluster, is not imprinted in mouse and is insensitive to the PWS-IC. Neurogenetics. 11: 145-151.
21.
Hogart A, Patzel KA, Lasalle JM: Gender influences monoallelic expression of ATP10A in human brain. Hum Genet. 2008
22.
Hogart A, Nagarajan RP, Patzel KA, Yasui DH, Lasalle JM: 15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. Hum Mol Genet. 2007, 16: 691-703.PubMedCentralCrossRefPubMed
23.
LaSalle J, Lalande M: Homologous association of oppositely imprinted chromosomal domains. Science. 1996, 272: 725-728. 10.1126/science.272.5262.725.CrossRefPubMed
24.
Meguro-Horike M, Yasui DH, Powell W, Schroeder DI, Oshimura M, Lasalle JM, Horike SI: Neuron-specific impairment of inter-chromosomal pairing and transcription in a novel model of human 15q-duplication syndrome. Hum Mol Genet. 2011
25.
Thatcher K, Peddada S, Yasui D, LaSalle JM: Homologous pairing of 15q11-13 imprinted domains in brain is developmentally regulated but deficient in Rett and autism samples. Hum Mol Genet. 2005, 14: 785-797. 10.1093/hmg/ddi073.CrossRefPubMed
26.
Hogart A, Leung KN, Wang NJ, Wu DJ, Driscoll J, Vallero RO, Schanen NC, LaSalle JM: Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number. J Med Genet. 2009, 46: 86-93.PubMedCentralCrossRefPubMed
27.
28.
29.
Bookout AL, Cummins CL, Mangelsdorf DJ, Pesola JM, Kramer MF: High-throughput real-time quantitative reverse transcription PCR. Curr Protoc Mol Biol. 2006, Chapter 15 (Unit 15): 18-
30.
Urraca N, Davis L, Cook EH, Schanen NC, Reiter LT: A single-tube quantitative high-resolution melting curve method for parent-of-origin determination of 15q duplications. Genet Test Mol Biomarkers. 2010, 14: 571-576. 10.1089/gtmb.2010.0030.PubMedCentralCrossRefPubMed
31.
Samaco RC, Hogart A, LaSalle JM: Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum Mol Genet. 2005, 14: 483-492.PubMedCentralCrossRefPubMed
32.
Mann SM, Wang NJ, Liu DH, Wang L, Schultz RA, Dorrani N, Sigman M, Schanen NC: Supernumerary tricentric derivative chromosome 15 in two boys with intractable epilepsy: another mechanism for partial hexasomy. Hum Genet. 2004, 115: 104-111.CrossRefPubMed
33.
Steffenburg S, Gillberg C, Hellgren L, Andersson L, Gillberg IC, Jakobsson G, Bohman M: A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry. 1989, 30: 405-416. 10.1111/j.1469-7610.1989.tb00254.x.CrossRefPubMed
34.
Herzing LBK, Cook EH, Ledbetter DH: Allele-specific expression analysis by RNA-FISH demonstrates preferential maternal expression of UBE3A and imprint maintenance within 15q11-q13 duplications. Hum Mol Genet. 2002, 11: 1707-1718. 10.1093/hmg/11.15.1707.CrossRefPubMed
35.
Baron CA, Tepper CG, Liu SY, Davis RR, Wang NJ, Schanen NC, Gregg JP: Genomic and functional profiling of duplicated chromosome 15 cell lines reveal regulatory alterations in UBE3A-associated ubiquitin-proteasome pathway processes. Hum Mol Genet. 2006, 15: 853-869. 10.1093/hmg/ddl004.CrossRefPubMed
36.
Nishimura Y, Martin CL, Vazquez-Lopez A, Spence SJ, Alvarez-Retuerto AI, Sigman M, Steindler C, Pellegrini S, Schanen NC, Warren ST, Geschwind DH: Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. Hum Mol Genet. 2007, 16: 1682-1698. 10.1093/hmg/ddm116.CrossRefPubMed
37.
Ehrlich M, Gama-Sosa MA, Huang LH, Midgett RM, Kuo KC, McCune RA, Gehrke C: Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells. Nucleic Acids Res. 1982, 10: 2709-2721. 10.1093/nar/10.8.2709.PubMedCentralCrossRefPubMed
38.
Schroeder DI, Lott P, Korf I, Lasalle JM: Large-scale methylation domains mark a functional subset of neuronally expressed genes. Genome Res. 2011
39.
Kriaucionis S, Heintz N: The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science. 2009, 324: 929-930. 10.1126/science.1169786.PubMedCentralCrossRefPubMed
40.
Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A: Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009, 324: 930-935. 10.1126/science.1170116.PubMedCentralCrossRefPubMed
41.
Ruzov A, Tsenkina Y, Serio A, Dudnakova T, Fletcher J, Bai Y, Chebotareva T, Pells S, Hannoun Z, Sullivan G: Lineage-specific distribution of high levels of genomic 5-hydroxymethylcytosine in mammalian development. Cell Res. 2011
42.
Guo JU, Su Y, Zhong C, Ming GL, Song H: Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell. 2011, 145: 423-434. 10.1016/j.cell.2011.03.022.PubMedCentralCrossRefPubMed
43.
Ficz G, Branco MR, Seisenberger S, Santos F, Krueger F, Hore TA, Marques CJ, Andrews S, Reik W: Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature. 2011, 473: 398-402. 10.1038/nature10008.CrossRefPubMed
44.
Ito S, D'Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y: Role of Tet proteins in 5 mC to 5 hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010, 466: 1129-1133. 10.1038/nature09303.PubMedCentralCrossRefPubMed
45.
Robertson J, Robertson AB, Klungland A: The presence of 5-hydroxymethylcytosine at the gene promoter and not in the gene body negatively regulates gene expression. Biochem Biophys Res Commun. 2011, 411: 40-43. 10.1016/j.bbrc.2011.06.077.CrossRefPubMed
46.
Ferdousy F, Bodeen W, Summers K, Doherty O, Wright O, Elsisi N, Hilliard G, O'Donnell JM, Reiter LT: Drosophila Ube3a regulates monoamine synthesis by increasing GTP cyclohydrolase I activity via a non-ubiquitin ligase mechanism. Neurobiol Dis. 41: 669-677.
47.
Makedonski K, Abuhatzira L, Kaufman Y, Razin A, Shemer R: MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression. Hum Mol Genet. 2005, 14: 1049-1058. 10.1093/hmg/ddi097.CrossRefPubMed
48.
Yasui DH, Peddada S, Bieda MC, Vallero RO, Hogart A, Nagarajan RP, Thatcher KN, Farnham PJ, Lasalle JM: Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes. Proc Natl Acad Sci USA. 2007, 104: 19416-19421. 10.1073/pnas.0707442104.PubMedCentralCrossRefPubMed
49.
Morrow EM: Genomic copy number variation in disorders of cognitive development. J Am Acad Child Adolesc Psychiatry. 2010, 49: 1091-1104.PubMedCentralPubMed
Metadata
Title
Increased copy number for methylated maternal 15q duplications leads to changes in gene and protein expression in human cortical samples
Authors
Haley A Scoles
Nora Urraca
Samuel W Chadwick
Lawrence T Reiter
Janine M LaSalle
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Molecular Autism / Issue 1/2011
Electronic ISSN: 2040-2392
DOI
https://doi.org/10.1186/2040-2392-2-19

Other articles of this Issue 1/2011

Molecular Autism 1/2011 Go to the issue

Short report

Investigation of the serum levels of anterior pituitary hormones in male children with autism

Research

Increased midgestational IFN-γ, IL-4 and IL-5 in women bearing a child with autism: A case-control study

Research

A quantitative association study of SLC25A12 and restricted repetitive behavior traits in autism spectrum disorders

Research

Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome

Review

Review of neuroimaging in autism spectrum disorders: what have we learned and where we go from here

Research

Further characterization of autoantibodies to GABAergic neurons in the central nervous system produced by a subset of children with autism