Replication of the Association of a MET Variant with Autism in a Chinese Han Population

Zhou, Xue; Xu, Yang; Wang, Jia; Zhou, Hongyu; Liu, Xian; Ayub, Qasim; Wang, Xuelai; Tyler‐Smith, Chris; Wu, Lijie; Xue, Yali

doi:10.1371/journal.pone.0027428

Cited by 21 publications

(18 citation statements)

References 35 publications

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“…Proband diagnosis and study inclusion criteria were completed as previously described [8]. The Autism Behavior Checklist (ABC) and Childhood Autism Rating Scale (CARS) were used for diagnosis.…”

Section: Methodsmentioning

confidence: 99%

Copy number variation in Han Chinese individuals with autism spectrum disorder

Gazzellone

Zhou

Lionel

et al. 2014

J Neurodevelop Disord

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BackgroundAutism spectrum disorders (ASDs) are a group of neurodevelopmental conditions with a demonstrated genetic etiology. Rare (<1% frequency) copy number variations (CNVs) account for a proportion of the genetic events involved, but the contribution of these events in non-European ASD populations has not been well studied. Here, we report on rare CNVs detected in a cohort of individuals with ASD of Han Chinese background.MethodsDNA samples were obtained from 104 ASD probands and their parents who were recruited from Harbin, China. Samples were genotyped on the Affymetrix CytoScan HD platform. Rare CNVs were identified by comparing data with 873 technology-matched controls from Ontario and 1,235 additional population controls of Han Chinese ethnicity.ResultsOf the probands, 8.6% had at least 1 de novo CNV (overlapping the GIGYF2, SPRY1, 16p13.3, 16p11.2, 17p13.3-17p13.2, DMD, and NAP1L6 genes/loci). Rare inherited CNVs affected other plausible neurodevelopmental candidate genes including GRID2, LINGO2, and SLC39A12. A 24-kb duplication was also identified at YWHAE, a gene previously implicated in ASD and other developmental disorders. This duplication is observed at a similar frequency in cases and in population controls and is likely a benign Asian-specific copy number polymorphism.ConclusionsOur findings help define genomic features relevant to ASD in the Han Chinese and emphasize the importance of using ancestry-matched controls in medical genetic interpretations.

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Section: Methodsmentioning

confidence: 99%

Copy number variation in Han Chinese individuals with autism spectrum disorder

Gazzellone

Zhou

Lionel

et al. 2014

J Neurodevelop Disord

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“…The probands diagnosis and study inclusion criteria were completed as previously described [9]. The Autism Behavior Checklist (ABC) and Childhood Autism Rating Scale (CARS) were used for the diagnosis.…”

Section: Experimental Procedures Sample Selectionmentioning

confidence: 99%

Copy number variations independently induce autism spectrum disorder

et al. 2017

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Correspondence : Sun Xiaofang (xiaofangsun@hotmail.com) The examination of copy number variation (CNV) is critical to understand the etiology of the CNV-related autism spectrum disorders (ASD). DNA samples were obtained from 64 ASD probands, which were genotyped on an Affymetrix CytoScan HD platform. qPCR or FISH were used as a validation for some novel recurrent CNVs. We further compared the clinical phenotypes of the genes in the Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER) database with these overlapping genes. Using vast, readily available databases with previously reported clinically relevant CNVs from human populations, the genes were evaluated using Enrichment Analysis and GO Slim Classification. By using the Ploysearch2 software, we identified the interaction relationship between significant genes and known ASD genes. A total of 29 CNVs, overlapping with 520 genes, including 315 OMIM genes, were identified. Additionally, myocyte enhancer factor 2 family (MEF2C) with two cases of CNV overlapping were also identified. Enrichment analysis showed that the 520 genes are most likely to be related to membrane components with protein-binding functions involved in metabolic processes. In the interaction network of those genes, the known ASD genes are mostly at the core position and the significant genes found in our samples are closely related to the known ASD genes. CNVs should be an independent factor to induce autism. With the strategy of our study, we could find the ASDs candidate genes by CNV data and review certain pathogenesis of this disorder. Those CNVs were associated with ASD and they may contribute to ASD by affecting the ASD-related genes.

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“…Our laboratory identified genetic association, in multiplex families, of a common promoter variant, rs1858830, in the gene encoding the MET receptor tyrosine kinase with ASD (15). The association of this and other variants has been replicated across independent cohorts (16–19). There are, however, two important facts to emphasize in our and others genetic findings.…”

Section: Genetic Studies: Association Of the Met Tyrosine Kinase Recementioning

confidence: 72%

The Pleiotropic MET Receptor Network: Circuit Development and the Neural-Medical Interface of Autism

Eagleson

Levitt

2017

Biological Psychiatry

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People with autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDDs) are behaviorally and medically heterogeneous. The combination of polygenicity and gene pleiotropy - the influence of one gene on distinct phenotypes - raises questions of how specific genes and their protein products interact to contribute to NDDs. A preponderance of evidence supports developmental and pathophysiological roles for the MET receptor tyrosine kinase, a multi-functional receptor that mediates distinct biological responses depending upon cell context. MET influences neuron architecture and synapse maturation in the forebrain, and regulates homeostasis in gastrointestinal and immune systems, both commonly disrupted in NDDs. Peak expression of synapse-enriched MET is conserved across rodent and primate forebrain, yet regional differences in primate neocortex are pronounced, with enrichment in circuits that participate in social information processing. A functional risk allele in the MET promoter, enriched in subgroups of children with ASD, reduces transcription and disrupts socially-relevant neural circuits structurally and functionally. In mice, circuit-specific deletion of Met causes distinct atypical behaviors. MET activation increases dendritic complexity and nascent synapse number, but synapse maturation requires reductions in MET. MET mediates its specific biological effects through different intracellular signaling pathways, and has a complex protein interactome that is enriched in ASD and other NDD candidates. The interactome is co-regulated in developing human neocortex. We suggest that a gene as pleiotropic and highly regulated as MET, together with its interactome, is biologically relevant in normal and pathophysiological contexts, impacting central and peripheral phenotypes that contribute to NDD risk and clinical symptoms.

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Replication of the Association of a MET Variant with Autism in a Chinese Han Population

Cited by 21 publications

References 35 publications

Copy number variation in Han Chinese individuals with autism spectrum disorder

Copy number variation in Han Chinese individuals with autism spectrum disorder

Copy number variations independently induce autism spectrum disorder

The Pleiotropic MET Receptor Network: Circuit Development and the Neural-Medical Interface of Autism

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