A genetic variant that disrupts MET transcription is associated with autism. Proc Natl Acad Sci USA

Department of Molecular Physiology and Biophysics, Vanderbilt University, Нашвилл, Michigan, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2006; 103(45):16834-9. DOI: 10.1073/pnas.0605296103
Source: PubMed


There is strong evidence for a genetic predisposition to autism and an intense interest in discovering heritable risk factors that disrupt gene function. Based on neurobiological findings and location within a chromosome 7q31 autism candidate gene region, we analyzed the gene encoding the pleiotropic MET receptor tyrosine kinase in a family based study of autism including 1,231 cases. MET signaling participates in neocortical and cerebellar growth and maturation, immune function, and gastrointestinal repair, consistent with reported medical complications in some children with autism. Here, we show genetic association (P = 0.0005) of a common C allele in the promoter region of the MET gene in 204 autism families. The allelic association at this MET variant was confirmed in a replication sample of 539 autism families (P = 0.001) and in the combined sample (P = 0.000005). Multiplex families, in which more than one child has autism, exhibited the strongest allelic association (P = 0.000007). In case-control analyses, the autism diagnosis relative risk was 2.27 (95% confidence interval: 1.41-3.65; P = 0.0006) for the CC genotype and 1.67 (95% confidence interval: 1.11-2.49; P = 0.012) for the CG genotype compared with the GG genotype. Functional assays showed that the C allele results in a 2-fold decrease in MET promoter activity and altered binding of specific transcription factor complexes. These data implicate reduced MET gene expression in autism susceptibility, providing evidence of a previously undescribed pathophysiological basis for this behaviorally and medically complex disorder.

Download full-text


Available from: Maurizio Elia
  • Source
    • "The diagnostic assessment for autism requires an elaborate screening process, which involves substantial consultations with many specialists and other physicians (Myers and Johnson 2007). The global prevalence of autism is estimated to be one in 160 people, and many studies have reported that the combination of genetic and environmental factors implicate a strong association in some aspects of ASD (Bailey et al. 1995; Campbell et al. 2006; Elsabbagh et al. 2012; Hallmayer et al. 2011); however, the development of ASD continues to be largely unclear. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The presentation of allergic diseases in children with autism spectrum disorder (ASD) was evaluated systematically through a literature search using MEDLINE, EMBASE, Cochrane Library, and CINAHL databases. Any comparative studies on children with ASD and allergic diseases were evaluated for eligibility followed by risk of bias assessment, data synthesis, and meta-analysis. No randomized clinical trials were identified but 10 eligible observational studies were found, all of low methodological quality. A high estimated prevalence of asthma (OR 1.69, 95 % CI 1.11 to 2.59; 2,191 ASD children) and atopic rhinitis (OR 1.66, 95 % CI 1.49 to 1.85; 1,973 ASD children) were indicated. Rates of food allergy did not show significant differences between groups. Currently, clinical evidence was not found to draw any specific clinical implication.
    Full-text · Article · Oct 2015
    • "According to Chen et al. (1996) HGF and Met family genes may indeed be physiological regulators of monocyte-macrophage differentiation/maturation . Besides that, the MET gene was also associated to the immune regulation in humans with autism (Campbell et al., 2006; Heuer et al., 2011). On the SSCX, no gene was found spanning a 100 kb upstream or downstream. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A genome-wide association study for immune response to influenza vaccination in a crossbred swine population was conducted. Swine influenza is caused by influenza A virus (FLUAV) which is considered one of the most prevalent respiratory pathogens in swine worldwide. The main strategy used to control influenza in swine herds is through vaccination. However, the currently circulating FLUAV subtypes in swine are genetically and antigenically diverse and their interaction with the host genetics poses a challenge for the production of efficacious and cross-protective vaccines. In this study, 103 pigs vaccinated with an inactivated H1N1 pandemic virus were genotyped with the Illumina PorcineSNP60V2 BeadChip for the identification of genetic markers associated with immune response efficacy to influenza A virus vaccination. Immune response was measured based on the presence or absence of HA (hemagglutinin) and NP (nucleoprotein) antibodies induced by vaccination and detected in swine sera by the hemagglutination inhibition (HI) and ELISA assays, respectively. The ELISA test was also used as a measurement of antibody levels produced following the FLUAV vaccination. Associations were tested with x(2) test for a case and control data and using maximum likelihood method for the quantitative data, where a moderate association was considered if p< 5×10(-5). When testing the association using the HI results, three markers with unknown location and three located on chromosomes SSCX, SSC14 and SSC18 were identified as associated with the immune response. Using the response to vaccination measured by ELISA as a qualitative and quantitative phenotype, four genomic regions were associated with immune response: one on SSC12 and three on chromosomes SSC1, SSC7, and SSC15, respectively. Those regions harbor important functional candidate genes possibly involved with the degree of immune response to vaccination. These results show an important role of host genetics in the immune response to influenza vaccination. Genetic selection for pigs with better response to FLUAV vaccination might be an alternative to reduce the impact of influenza virus infection in the swine industry. However, these results should to be validated in additional populations before its use.
    No preview · Article · Sep 2015 · Virus Research
  • Source
    • "MiR-133b and miR-206, located in the same cluster, are strong candidate genes for ASD on the basis of their functional role. Both miRNAs regulate the proto-oncogene MET (Taulli et al. 2009; Yan et al. 2009; Hu et al. 2010), which has consistently been associated with autism (Campbell et al. 2006; Sousa et al. 2009; Thanseem et al. 2010). Although the miR-133b/miR-206 cluster was initially considered to have muscle-specifi c expression, recent studies indicate that miR-133b regulates differentiation and maturation of dopaminergic neurons (Hebert and de Strooper 2009), whereas miR-206 regulates BDNF , a key regulator of synaptic plasticity (Lee et al. 2012), and is highly expressed in rat cerebellum (Olsen et al. 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs (miRNAs) are post-transcriptional regulators that have been shown to be involved in disease susceptibility. Here we explore the possible contribution of common and rare variants in miRNA genes in autism spectrum disorders (ASD). A total of 350 tag SNPs from 163 miRNA genes were genotyped in 636 ASD cases and 673 controls. A replication study was performed in a sample of 449 ASD cases and 415 controls. Additionally, rare variants in 701 miRNA genes of 41 ASD patients were examined using whole-exome sequencing. The most significant association in the discovery sample was obtained for the miR-133b/miR-206 cluster (rs16882131, P = 0.00037). The replication study did not reach significance. However, the pooled analysis (1,085 cases and 1,088 controls) showed association with two miRNA clusters: miR-133b/miR-206 (rs16882131, permP = 0.037) and miR-17/miR-18a/miR-19a/miR-20a/miR-19b-1/miR92a-1 (rs6492538, permP = 0.019). Both miR-133b and miR-206 regulate the MET gene, previously associated with ASD. Rare variant analysis identified mutations in several miRNA genes, among them miR-541, a brain-specific miRNA that regulates SYN1, found mutated in ASD. Although our results do not establish a clear role for miRNAs in ASD, we pinpointed a few candidate genes. Further exome and GWAS studies are warranted to get more insight into their potential contribution to the disorder.
    Full-text · Article · Apr 2015 · The World Journal of Biological Psychiatry
Show more