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

Department of Pharmacology, Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37203, USA.
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.

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Available from: Maurizio Elia, Oct 01, 2015
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    • "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). "
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    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.
    The World Journal of Biological Psychiatry 04/2015; DOI:10.3109/15622975.2015.1029518 · 4.18 Impact Factor
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    • "Rather than treating ASD as discrete entities with a categorical approach based on a distinct boundary between normality and pathology, several authors [4] [5] have suggested a dimensional approach to ASD, which conceptualises these disorders as the upper extreme of a constellation of deficits in social adaptation and communication that may be continuously distributed in the population . There are several lines of evidence for this notion: autistic traits measured in the general population show a smooth distribution throughout the normal range to the clinical extreme [6] [7]; relatives of patients with ASD display high levels of autistic traits [8] [9]; factor analytic approaches did not detect discontinuities between ASD and autistic traits [10]; known risk factors for ASD (e.g., paternal age at birth) have been shown to influence autistic traits [11]; common genetic variants that are, by their very nature, present in a significant proportion of the general population, are believed to play a role in the aetiology of ASD [12] [13] [14]. Indeed, the DSM-5 itself has highlighted the dimensional nature of the cardinal behavioural domains of ASD, by incorporating a severity scale to capture the 'spectrum' nature of ASD [1]. "
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    ABSTRACT: Background: In recent years, several twin studies adopted a dimensional approach to Autism Spectrum Disorders (ASD) and estimated the contribution of genetic and environmental influences to variation in autistic traits. However, no study was performed on adults over 18 years of age and all but two studies were based on parent or teacher ratings. Also, the genetic and environmental contributions to the interplay between autistic traits and adult personality dimensions have not been investigated. Methods: A sample of 266 complete twin pairs (30% males, mean age 40 ± 12 years) drawn from the population-based Italian Twin Register was administered the Autism-Spectrum Quotient, Temperament and Character Inventory (TCI-125), and General Health Questionnaire (GHQ-12). Genetic structural equation modelling was performed with the Mx program. Estimates were adjusted for gender, age, and GHQ-12 score. Results: Genetic factors accounted for 44% and 20%-49% of individual differences in autistic traits and TCI dimensions, respectively. Unshared environmental factors explained the remaining proportion of variance. Consistently with the notion of a personality profile in ASD characterised by obsessive temperament, autistic traits showed significant phenotypic correlations with several TCI dimensions (positive: HA; negative: NS, RD, SD, C). Genetic and unshared environmental correlations between AQ and these TCI dimensions were significant. The degree of genetic overlap was generally greater than the degree of environmental overlap. Conclusions: Despite some limitations, this study suggests that genetic factors contribute substantially to individual differences in autistic traits in adults, with unshared environmental influences also playing an important role. It also suggests that autistic traits and the majority of temperament and character dimensions share common genetic and environmental aetiological factors.
    Comprehensive Psychiatry 12/2014; 58. DOI:10.1016/j.comppsych.2014.12.018 · 2.25 Impact Factor
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    • "The Ras/Raf/ERK pathway can be activated by LTP-inducing stimuli to phosphorylate AMPARs with long cytoplasmic termini and drive these receptors into synapses. Importantly, recent studies have reported a number of genes including receptor tyrosine kinases (RTKs), phosphatase and tensin homolog (PTEN) and SH3 and multiple ankyrin repeat domains protein 3 (Shank3) to be associated with autism (Goffin et al., 2001; Butler et al., 2005; Campbell et al., 2006; Durand et al., 2007b), with these genes shown to converge on ERK signaling (McKay and Morrison, 2007; Chalhoub et al., 2009; Levitt and Campbell, 2009). Thus, we presume the alteration in Ras/Raf/ERK signaling in BTBR mice could contribute to the autistic-like behaviors in this strain through its impairment on synapse development and functioning. "
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    ABSTRACT: BTBR mice exhibit several autistic-like behaviors and are currently used as a model for understanding mechanisms that may be responsible for the pathogenesis of autism. Ras/Raf/ERK1/2 signaling has been suggested to play an important role in neural development, learning, memory, and cognition. Two studies reported that a deletion of a locus on chromosome 16 containing the mitogen-activated protein kinase 3 (MAPK3) gene, which encodes ERK1, is associated with autism. In the present study, Ras/Raf/ERK1/2 signaling was found to be up-regulated in BTBR mice relative to matched control B6 mice, to further suggest involvement in the pathogenesis of autism. To further characterize the developmental pattern of Ras/Raf/ERK1/2 signaling, varying stages during development were sampled to reveal an up-regulation in newborn and 2-week old BTBR mice relative to age-matched B6 mice. By the age of 3-week, Ras/Raf/ERK1/2 signaling in the brain of BTBR mice was unaltered relative to B6 mice, with this trend maintained in 6-week samples. These results suggest that the alteration of Ras/Raf/ERK signaling in the early developmental stages in mice could contribute to the noted autistic phenotype. Furthermore, these findings support the value of BTBR mice to serve as a human analogue for autistic etiological research and aid in a better understanding of the developmental mechanisms of autism.
    International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 12/2014; 39. DOI:10.1016/j.ijdevneu.2014.01.006 · 2.58 Impact Factor
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