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

• Published in: Molecular autism Vol. 8; no. 1; p. 43
• Main Authors: Wen, Zhu, Cheng, Tian-Lin, Li, Gai-Zhi, Sun, Shi-Bang, Yu, Shun-Ying, Zhang, Yi, Du, Ya-Song, Qiu, Zilong
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 03.08.2017; BioMed Central; BMC
• Subjects: Adolescent; Ataxia; Autism; Autism spectrum disorder; Autistic Disorder - genetics; Autistic Disorder - metabolism; Behavior; Care and treatment; Child; Child & adolescent psychiatry; Child, Preschool; Deoxyribonucleic acid; Diagnosis; DNA; DNA Mutational Analysis; DNA sequencing; Female; Fluorescent Antibody Technique; Gene mutations; Genetic aspects; Genetic Association Studies; Genetic Loci; Genetic Predisposition to Disease; Health aspects; Heterozygote; Humans; Intellectual disabilities; Male; Mental disorders; Mental health; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Methyl-CpG-binding protein-2 (MeCP2); Mutation; Neural development; Neurodevelopmental disorders; Neurosciences; Nucleotide sequencing; Patients; Pedigree; Physiological aspects; Proteins; Psychosis; Whole Exome Sequencing; China; Methyl-CpG-binding protein-2 (MeCP2); Whole-exome sequencing; Autism spectrum disorder; Neural development
• ISSN: 2040-2392; 2040-2392
• DOI: 10.1186/s13229-017-0157-5

Methyl-CpG-binding protein-2 (MeCP2) is a critical regulator for neural development. Either or leads to severe neurodevelopmental disorders, such as Rett syndrome (RTT) and autism spectrum disorder (ASD). We set out to screen for mutations in patients of ASD and determine whether these autism-related mutations may compromise the proper function of MeCP2. Whole-exome sequencing was performed to screen and other ASD candidate genes for 120 patients diagnosed with ASD. The parents of patients who were identified with 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. We identified three missense mutations of 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 mutations impair the proper development of neurons. Our study identified genetic mutations of the gene in autism patients, which were previously considered to be associated primarily with RTT. This finding suggests that loss-of-function mutations of may also lead to autism spectrum disorders.