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Identification of Autism-Related MECP2 Mutations by Whole-Exome

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Identification of Autism-Related MECP2 Mutations by Whole-Exome Wen et al. Molecular Autism (2017) 8:43 DOI 10.1186/s13229-017-0157-5 RESEARCH Open Access Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation Zhu Wen1, Tian-Lin Cheng2, Gai-zhi Li1, Shi-Bang Sun1, Shun-Ying Yu1, Yi Zhang3,4*, Ya-Song Du1* and Zilong Qiu2* Abstract Background: Methyl-CpG-binding protein-2 (MeCP2) is a critical regulator for neural development. Either loss- or gain-of-function leads to severe neurodevelopmental disorders, such as Rett syndrome (RTT) and autism spectrum disorder (ASD). We set out to screen for MECP2 mutations in patients of ASD and determine whether these autism-related mutations may compromise the proper function of MeCP2. Methods: Whole-exome sequencing was performed to screen MECP2 and other ASD candidate genes for 120 patients diagnosed with ASD. The parents of patients who were identified with MECP2 mutation were selected for further Sanger sequencing. Each patient accomplished the case report form including general information and clinical scales applied to assess their clinical features. Mouse cortical neurons and HEK-293 cells were cultured and transfected with MeCP2 wild-type (WT) or mutant to examine the function of autism-associated MeCP2 mutants. HEK-293 cells were used to examine the expression of MeCP2 mutant constructs with Western blot. Mouse cortical neurons were used to analyze neurites and axon outgrowth by immunofluorescence experiments. Results: We identified three missense mutations of MECP2 from three autism patients by whole-exome sequencing: p.P152L (c.455C>T), p.P376S (c.1162C>T), and p.R294X (c.880C>T). Among these mutations, p.P152L and p.R294X were de novo mutations, whereas p.P376S was inherited maternally. The diagnosis of RTT was excluded in all three autism patients. Abnormalities of dendritic and axonal growth were found after autism-related MeCP2 mutants were expressed in mouse cortical neurons; suggesting that autism-related MECP2 mutations impair the proper development of neurons. Conclusions: Our study identified genetic mutations of the MECP2 gene in autism patients, which were previously considered to be associated primarily with RTT. This finding suggests that loss-of-function mutations of MECP2 may also lead to autism spectrum disorders. Keywords: Autism spectrum disorder, Methyl-CpG-binding protein-2 (MeCP2), Whole-exome sequencing, Neural development * Correspondence: [email protected]; [email protected]; [email protected] 3School of Life Sciences, Peking University, Beijing, China 1Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China 2Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wen et al. Molecular Autism (2017) 8:43 Page 2 of 10 Background Tong University (FWA number 00003065, IROG num- Autism spectrum disorder (ASD) comprises a set of hetero- ber 0002202). Dr. Yi-Feng Xu approved and signed our geneous neurodevelopmental diseases characterized by study with ethical review number 2016–4. Written early-onset difficulties in social communication/interaction informed consent was obtained from parents in consid- and repetitive, restricted behavior/interests [1, 2]. eration of the fact that all patients were minors. All par- According to a meta-analysis in China, the prevalence of ticipants were screened using the appropriate protocol autism is approximately 12.8 per 1000 individuals [3]. approved by the IRB. Methyl-CpG-binding protein 2 (MeCP2) is a critical regulator for brain development. Mutations of the MECP2 Subjects gene lead to Rett syndrome (RTT), whereas duplications of A total of 120 core families with probands diagnosed MECP2-containing genomic segments cause the MECP2 with ASD were recruited from the outpatient Depart- duplication syndrome [4, 5]. More than 95% of patients ment of the Child and Adolescent Psychiatry, Shanghai with RTT carry mutations in MECP2 [6–9]. Mutations Mental Health Center from 2013 to 2015. All patients have also been reported in a few patients diagnosed with were diagnosed on the basis of the fourth edition of the autism spectrum disorders [10–12]. However, whether Diagnostic and Statistical Manual of Mental Disorders MECP2 mutations identified in patients with autism inter- (DSM-IV) [23]. All patients were Han Chinese and their fere with normal functions of MeCP2 remained unknown. mean age was 78 months with ranged from 2 to 18 years. Regarding to clinical symptoms, there are some over- Among them, 102 were males and 18 were females. Any lapping phenotypes between ASD and RTT, including patient suffering a severe somatic disorder (including social avoidance, stereotypic body/hand movement, and cardiomyopathy, tumor, and epilepsy) was excluded; those anxiety [13]. Furthermore, some girls with RTT also with a family history of psychosis were also excluded. meet the criteria for ASD [14]. However, the core symp- toms of RTT such as defects in locomotor activity and Clinical scale assessment repetitive seizure are normally not often seen in ASD For each patient, we collected a comprehensive profile patients. There are severe autistic features identified in including a detailed developmental history, clinical boys with the MECP2 duplication syndrome [15]. history, phenotypic features, family background, and − In Mecp2 null (Mecp2 /y) mice, severe neurological scale examination. These were collected in the case phenotypic features, including hypoactivity, seizures, report form (CRF). In CRF, all symptoms are classified motor dysfunction, ataxia, and early death (8–10 weeks), into four parts in accordance with diagnostic items of were found [16, 17]. MECP2 transgenic mice showed ASD in DSM-IV: social interaction, language, repetitive be- progressive neurological phenotypes including seizures, haviors, and functional impairment. Scales were applied to as- motor dysfunction, ataxia, and stereotypic behaviors sess patients’ symptoms including Child Autism Rating Scale [18]. Autistic-like behaviors (stereotypies and social be- Score (CARS) and Autism behavior checklist (ABC). A cutoff havior abnormalities) were also observed in Mecp2308/Y score of CARS >36 represented severe autism, and a cutoff mouse models and transgenic monkeys overexpressing score of ABC >67 pointed to a high probability of autism. MECP2 [19, 20]. In this study, we performed whole-exome sequencing Whole-exome sequencing on 120 ASD cases and identified three missense muta- DNA extraction and quality control of sample DNA tions in coding regions of the MECP2 gene. The MECP2 DNA was extracted from peripheral blood of patients gene is associated with a host of neuropsychiatric disor- and their parents using the DNeasy Blood &Tissue Kit ders and neurological phenotypes. Moreover, MECP2 (Cat no. 69506, QIAGEN, GmBH, Germany), following the mutations have been described in RTT, autism, mental manufacturer’s instructions. Qubit 2.0 Fluorometer (Cat retardation, and early-onset psychosis [11, 13, 21, 22]. no. Q32866, Invitrogen) was used to identify the quantity We therefore hypothesized that mutations of MECP2 in of purified DNA, and additional 1% agarose gel electro- Chinese Han patients may be one of key contributors to phoresis was performed to check the size integrity of puri- ASD. We provided functional evidences and further fied DNA. Samples were excluded if the total mass, suggested that genetic mutations associated with MECP2 concentration, integrity of DNA, or quality of preliminary may shed light on the pathogenesis of autism and related genotyping data was too low. Typical 2–3 μggenomic neuropsychiatric disorders. DNA was used for each WES experiments. Methods Library preparation and assessment Ethics statement For each sample to be sequenced, individual library We obtained assent from the Institutional Review Board preparations, hybridizations, and captures were per- (IRB), Shanghai Mental Health Center of Shanghai Jiao formed following the protocol of the SureSelectXT Wen et al. Molecular Autism (2017) 8:43 Page 3 of 10 Target Enrichment System for Illumina Paired-End Variant Recalibrator and Apply Recalibration of GATK, Sequencing Library (Agilent Technologies, Inc., Santa coverage was over 90%, and reads on target region (%) Clara, CA) to assess quantity of library with Qubit 2.0 was over 94%. Second, we required that variant location at Fluoromete. The 2100 Bioanalyzer High Sensitivity DNA exon or splicing site. Third, we selected exonic Function Assay was used to assess the quality and size range as including non-synonymous SNV, stopgain/loss, startgain/ instructed in the reagent kit guide. loss splice site, and frameshift. Fourth, MAF ≤ 1% or null in 1000G-ASN. Finally, the results of primary analysis by Preparation of libraries for cluster
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