Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validationReport as inadecuate

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Molecular Autism

, 8:43

First Online: 03 August 2017Received: 13 February 2017Accepted: 07 July 2017


BackgroundMethyl-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.

MethodsWhole-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.

ResultsWe 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.

ConclusionsOur 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.

KeywordsAutism spectrum disorder Methyl-CpG-binding protein-2 MeCP2 Whole-exome sequencing Neural development AbbreviationsABCAutism Behavior Checklist

ADI-RAutism diagnostic interview-revised

ASDAutism spectrum disorder

CARSChild Autism Rating Scale score

CDDChildhood disintegrative disorder

DSM-IVDiagnostic and statistical manual of mental disorders fourth edition

MPS IIIAMucopolysaccharidosis IIIA

MRIMagnetic resonance imaging

PDDPervasive developmental disorder

uGAGUrinary glycosaminoglycan

WESWhole-exome sequencing

Electronic supplementary materialThe online version of this article doi:10.1186-s13229-017-0157-5 contains supplementary material, which is available to authorized users.

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Author: Zhu Wen - Tian-Lin Cheng - Gai-zhi Li - Shi-Bang Sun - Shun-Ying Yu - Yi Zhang - Ya-Song Du - Zilong Qiu


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