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Molecular Autism
Published in: Molecular Autism 1/2016

Open Access 01-12-2016 | Research

Genome-wide analysis of copy number variations identifies PARK2 as a candidate gene for autism spectrum disorder

Authors: Chia-Lin Yin, Hsin-I Chen, Ling-Hui Li, Yi-Ling Chien, Hsiao-Mei Liao, Miao Chun Chou, Wen-Jiun Chou, Wen-Che Tsai, Yen-Nan Chiu, Yu-Yu Wu, Chen-Zen Lo, Jer-Yuarn Wu, Yuan-Tsong Chen, Susan Shur-Fen Gau

Published in: Molecular Autism | Issue 1/2016

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Abstract

Background

Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder with complex genetic underpinning in its etiology. Copy number variations (CNVs) as one of the genetic factors associated with ASD have been addressed in recent genome-wide association studies (GWAS). However, the significance of CNV has not been well investigated in non-Caucasian ASD population.

Methods

To identify the pathogenic CNVs responsible for ASD in Han Chinese, we performed a segment-based GWAS of CNV in 335 ASD cases and 1093 healthy controls using Affymetrix single nucleotide polymorphism (SNP) array by focusing on case-specific CNVs. PARK2 was one of the important genes with several case-specific regions overlapped on it. The findings were validated in the initial screen sample set and replicated in another sample set by real-time quantitative PCR (qPCR).

Results

A total of six CNVs at 6q26 that spanned different exons of PARK2 were identified. The PARK2 expression level was down-regulated at exon-dependent manner in cases with either deletion or duplication. The result revealed that the gene function might be disrupted by exonic deletion and duplication. We also observed that the ASD case with exonic duplication demonstrated a more severe interference of PARK2 expression and the clinical feature than the ones with deletion at the exons 2–4 of the PARK2 gene.

Conclusions

Our finding provides evidence to support that CNVs affecting PARK2 function might contribute to genetic etiology of a proportion of cases with ASD. The intriguing results of this work warrant further study on characterizing the functional impact of various exonic CNVs on the PARK2 gene.

Trial registration

ClinicalTrials.gov NCT00494754
Appendix
Available only for authorised users
Literature
1.
Gmitrowicz A, Kucharska A. [Developmental disorders in the fourth edition of the American classification: diagnostic and statistical manual of mental disorders (DSM IV—optional book)]. Psychiatr Pol. 1994;28:509–21.PubMed
2.
Kim YS, Leventhal BL, Koh YJ, Fombonne E, Laska E, Lim EC, et al. Prevalence of autism spectrum disorders in a total population sample. Am J Psychiatry. 2011;168:904–12.CrossRefPubMed
3.
4.
5.
Shishido E, Aleksic B, Ozaki N. Copy-number variation in the pathogenesis of autism spectrum disorder. Psychiatry Clin Neurosci. 2014;68:85–95.CrossRefPubMed
6.
7.
Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, et al. Strong association of de novo copy number mutations with autism. Science. 2007;316:445–9.CrossRefPubMedPubMedCentral
8.
Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010;466:368–72.CrossRefPubMedPubMedCentral
9.
Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron. 2011;70:863–85.CrossRefPubMedPubMedCentral
10.
Jamain S, Quach H, Betancur C, Rastam M, Colineaux C, Gillberg IC, et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet. 2003;34:27–9.CrossRefPubMedPubMedCentral
11.
Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet. 2007;39:25–7.CrossRefPubMedPubMedCentral
12.
Dykens EM, Sutcliffe JS, Levitt P. Autism and 15q11-q13 disorders: behavioral, genetic, and pathophysiological issues. Ment Retard Dev Disabil Res Rev. 2004;10:284–91.CrossRefPubMed
13.
Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392:605–8.CrossRefPubMed
14.
Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M. Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet. 2008;40:880–5.CrossRefPubMed
15.
Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature. 2009;459:569–73.CrossRefPubMedPubMedCentral
16.
Jarick I, Volckmar AL, Putter C, Pechlivanis S, Nguyen TT, Dauvermann MR, et al. Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder. Mol Psychiatry. 2014;19:115–21.CrossRefPubMedPubMedCentral
17.
Scheuerle A, Wilson K. PARK2 copy number aberrations in two children presenting with autism spectrum disorder: further support of an association and possible evidence for a new microdeletion/microduplication syndrome. Am J Med Genet B Neuropsychiatr Genet. 2011;156B:413–20.CrossRefPubMed
18.
Gau SS, Liu LT, Wu YY, Chiu YN, Tsai WC. Psychometric properties of the Chinese version of the social responsiveness scale. Res Autism Spectr Disord. 2013;7:349–60.CrossRef
19.
Liao HM, Gau SS, Tsai WC, Fang JS, Su YC, Chou MC, et al. Chromosomal abnormalities in patients with autism spectrum disorders from Taiwan. Am J Med Genet B Neuropsychiatr Genet. 2013;162B:734–41. doi:10.​1002/​ajmg.​b.​32153.CrossRefPubMed
20.
Pan WH, Fann CS, Wu JY, Hung YT, Ho MS, Tai TH, et al. Han Chinese cell and genome bank in Taiwan: purpose, design and ethical considerations. Hum Hered. 2006;61:27–30.CrossRefPubMed
21.
Devlin B, Scherer SW. Genetic architecture in autism spectrum disorder. Curr Opin Genet Dev. 2012;22:229–37.CrossRefPubMed
22.
Marshall CR, Scherer SW. Detection and characterization of copy number variation in autism spectrum disorder. Methods Mol Biol. 2012;838:115–35.CrossRefPubMed
23.
Menashe I, Larsen EC, Banerjee-Basu S. Prioritization of copy number variation loci associated with autism from AutDB—an integrative multi-study genetic database. PLoS One. 2013;8, e66707.CrossRefPubMedPubMedCentral
24.
Sener EF. Association of copy number variations in autism spectrum disorders: a systematic review. Chinese J Biol. 2014;2014:2014.CrossRef
25.
Exner N, Lutz AK, Haass C, Winklhofer KF. Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J. 2012;31:3038–62.CrossRefPubMedPubMedCentral
26.
Batlevi Y, La Spada AR. Mitochondrial autophagy in neural function, neurodegenerative disease, neuron cell death, and aging. Neurobiol Dis. 2011;43:46–51.CrossRefPubMedPubMedCentral
27.
Huynh DP, Scoles DR, Ho TH, Del Bigio MR, Pulst SM. Parkin is associated with actin filaments in neuronal and nonneural cells. Ann Neurol. 2000;48:737–44.CrossRefPubMed
28.
Shin JH, Ko HS, Kang H, Lee Y, Lee YI, Pletinkova O, et al. PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson’s disease. Cell. 2011;144:689–702.CrossRefPubMedPubMedCentral
29.
Huttenlocher J, Stefansson H, Steinberg S, Helgadottir HT, Sveinbjornsdottir S, Riess O, et al. Heterozygote carriers for CNVs in PARK2 are at increased risk of Parkinson’s disease. Hum Mol Genet. 2015;24:5637–43.CrossRefPubMed
30.
Kay DM, Stevens CF, Hamza TH, Montimurro JS, Zabetian CP, Factor SA, et al. A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2. Neurology. 2010;75:1189–94.CrossRefPubMedPubMedCentral
31.
Mariani M, Crosti F, Redaelli S, Fossati C, Piras R, Biondi A, et al. Partial duplication of the PARK2 gene in a child with developmental delay and her normal mother: a second report. Am J Med Genet B Neuropsychiatr Genet. 2013;162B:485–6.CrossRefPubMed
32.
Riley BE, Lougheed JC, Callaway K, Velasquez M, Brecht E, Nguyen L, et al. Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases. Nat Commun. 2013;4:1982.CrossRefPubMedPubMedCentral
33.
34.
Hristova VA, Beasley SA, Rylett RJ, Shaw GS. Identification of a novel Zn2 + -binding domain in the autosomal recessive juvenile Parkinson-related E3 ligase parkin. J Biol Chem. 2009;284:14978–86.CrossRefPubMedPubMedCentral
35.
Anitha A, Nakamura K, Thanseem I, Yamada K, Iwayama Y, Toyota T, et al. Brain region-specific altered expression and association of mitochondria-related genes in autism. Mol Autism. 2012;3:12.CrossRefPubMedPubMedCentral
36.
Shimura H, Hattori N, Kubo S, Yoshikawa M, Kitada T, Matsumine H, et al. Immunohistochemical and subcellular localization of Parkin protein: absence of protein in autosomal recessive juvenile parkinsonism patients. Ann Neurol. 1999;45:668–72.CrossRefPubMed
Metadata
Title
Genome-wide analysis of copy number variations identifies PARK2 as a candidate gene for autism spectrum disorder
Authors
Chia-Lin Yin
Hsin-I Chen
Ling-Hui Li
Yi-Ling Chien
Hsiao-Mei Liao
Miao Chun Chou
Wen-Jiun Chou
Wen-Che Tsai
Yen-Nan Chiu
Yu-Yu Wu
Chen-Zen Lo
Jer-Yuarn Wu
Yuan-Tsong Chen
Susan Shur-Fen Gau
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Molecular Autism / Issue 1/2016
Electronic ISSN: 2040-2392
DOI
https://doi.org/10.1186/s13229-016-0087-7

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