Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation

Mol Autism. 2017 Aug 3;8:43. doi: 10.1186/s13229-017-0157-5. eCollection 2017.


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); Neural development; Whole-exome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Autistic Disorder / genetics*
  • Autistic Disorder / metabolism
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Female
  • Fluorescent Antibody Technique
  • Genetic Association Studies
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Heterozygote
  • Humans
  • Male
  • Methyl-CpG-Binding Protein 2 / genetics*
  • Methyl-CpG-Binding Protein 2 / metabolism
  • Mutation*
  • Pedigree
  • Whole Exome Sequencing


  • MECP2 protein, human
  • Methyl-CpG-Binding Protein 2