Aperçu: G.M.
Plusieurs
domaines de facteur de croissance épidermique 10 (MEGF10), un membre
critique de la voie d'engouement apoptotique, agissent comme médiateur de l'élagage des
axones et de l'élimination des synapses lors du développement du
cerveau. Des études antérieures ont indiqué que le déficit d'élagage synaptique était associé à des phénotypes liés à l'autisme. Toutefois, la relation entre le MEGF10 et l'autisme reste mal comprise.
Pour
étudier le rôle des variantes de MEGF10 avec une fonction putative de
régulation de la transcription dans l'étiologie de l'autisme, les chercheurs ont effectué une étude d'association familiale dans 410 trios chinois Han. Les résultats indiquent que trois polymorphismes nucléotidiques (SNP),
rs4836316, rs2194079 et rs4836317 près du TSS (transcription start site) sont significativement
associés à l'autisme.
Sci Rep. 2017 May 23;7(1):2292. doi: 10.1038/s41598-017-02348-1.
Genetic variants in the transcription regulatory region of MEGF10 are associated with autism in Chinese Han population
Wu Z1,2, Qin J3, You Y1,2, Ma Y4,5, Jia M1,2, Wang L1,2, Lu T1,2, Yue W1,2, Ruan Y1,2, Zhang D1,2,4,5, Li J6,7, Wang L8,9.
Author information
- 1
- Institute of Mental Health, The Sixth Hospital, Peking University, Beijing, P. R. China.
- 2
- Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, P.R. China.
- 3
- Central Laboratory, Renmin Hospital, Wuhan University, Wuhan, Hubei, P. R. China.
- 4
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, P. R. China.
- 5
- PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, P. R. China.
- 6
- Institute of Mental Health, The Sixth Hospital, Peking University, Beijing, P. R. China. junli1985@bjmu.edu.cn.
- 7
- Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, P.R. China. junli1985@bjmu.edu.cn.
- 8
- Institute of Mental Health, The Sixth Hospital, Peking University, Beijing, P. R. China. lifangwang@bjmu.edu.cn.
- 9
- Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, P.R. China. lifangwang@bjmu.edu.cn.
Abstract
Multiple
epidermal growth factor-like-domains 10 (MEGF10), a critical member of
the apoptotic engulfment pathway, mediates axon pruning and synapse
elimination during brain development. Previous studies indicated that
synaptic pruning deficit was associated with autism-related phenotypes.
However, the relationship between MEGF10 and autism remains poorly
understood. Disease-associated variants are significantly enriched in
the transcription regulatory regions. These include the transcription
start site (TSS) and its cis-regulatory elements. To investigate the
role of MEGF10 variants with putative transcription regulatory function
in the etiology of autism, we performed a family-based association study
in 410 Chinese Han trios. Our results indicate that three single
nucleotide polymorphisms (SNPs), rs4836316, rs2194079 and rs4836317 near
the TSS are significantly associated with autism following Bonferroni
correction (p = 0.0011, p = 0.0088, and p = 0.0023, respectively).
Haplotype T-A-G (rs4836316-rs2194079-rs4836317) was preferentially
transmitted from parents to affected offspring (p permutation = 0.0055).
Consistently, functional exploration further verified that the risk
allele and haplotype might influence its binding with transcription
factors, resulting in decreased transcriptional activity of MEGF10. Our
findings indicated that the risk alleles and haplotype near the MEGF10
TSS might modulate transcriptional activity and increase the
susceptibility to autism.
- PMID:28536440
- PMCID:PMC5442155
- DOI: 10.1038/s41598-017-02348-1
