Article

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

ABSTRACT

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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    • "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. "
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    • "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. "
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