MET and autism susceptibility: family and case–control studies

Abstract

Autism is a common, severe and highly heritable neurodevelopmental disorder. The International Molecular Genetic Study of Autism Consortium (IMGSAC) genome screen for linkage in affected sib-pair families identified a chromosome 7q susceptibility locus (AUTS1), that has subsequently shown evidence of increased sharing in several independent multiplex samples and in two meta-analyses. Taking into account the location of the MET gene under this linkage peak, and the fact that it has recently been reported to be associated with autism, the gene was further analyzed as a promising autism candidate. The gene encodes a transmembrane receptor tyrosine kinase of the hepatocyte growth factor/scatter factor (HGF/SF). MET is best known as an oncogene, but its signalling also participates in immune function, peripheral organ development and repair, and the development of the cerebral cortex and cerebellum (all of which have been observed earlier as being disregulated in individuals with autism). Here we present a family-based association analysis covering the entire MET locus. Significant results were obtained in both single locus and haplotype approaches with a single nucleotide polymorphism in intron 1 (rs38845, Po0.004) and with one intronic haplotype (AAGTG, Po0.009) in 325 multiplex IMGSAC families and 10 IMGSAC trios. Although these results failed to replicate in an independent sample of 82 Italian trios, the association itself was confirmed by a case-control analysis performed using the Italian cohort (Po0.02). The previously reported positive association of rs1858830 failed to replicate in this study. Overall, our findings provide further evidence that MET may play a role in autism susceptibility.

When linkage signal for autism MET candidate gene

“…Sousa et al report association of a potential functional variant of the MET gene with autism in two patient samples. 1 These results increase to five the cohorts in which variants of the MET gene are reported to be associated with autism, suggesting that the MET receptor tyrosine kinase and the molecular cascade through which it signals contribute to autism risk.…”

“…5 The results of Sousa et al failed to replicate genetic association of the rs1858830 C allele, but identified association of another allele with a similar potential to regulate the expression of the MET gene. 1 1 Although direct evidence to indicate function of the rs38845 A allele is not presented, Sousa et al 1 discuss in silico evidence that the A allele creates a binding site for the transcription factor IRF1, and present a hypothesis of how the A allele may contribute to decreased MET protein expression in individuals with autism. In addition to the SNP alleles that may regulate transcription, rare de novo copy number variation losses of the chromosomal region including the MET gene have also been reported.…”

“…There are a number of reasons for the difficulty in identifying the chromosome 7q autism risk genes, including genetic and phenotypic heterogeneityFnot all cases of autism are impacted by the same genetic variation and the same genetic variation may not always result in autism. Further compounding difficulties in identifying the autism risk genes on chromosome 7q is the broad linkage peak that includes over 200 mapped genes, 1 and evidence that there may be multiple overlapping linkage signals that contribute to the peak. 3 Consistent with the existence of multiple genes contributing to overlapping linkage signals, evidence of genetic association with autism have been reported for genes located in three different regions of the broad peak: at chromosome 7q21 (RELN, SERPINE1), chromosome 7q31 (MET) and chromosome 7q35 -36 (CNTNAP2, EN2).…”

The Genetics of Autism Spectrum Disorders

“…The oncogene MET is also strongly linked to ASD etiology, having been supported by a number of studies in the past decade (e.g. IMGSAC, 2001;Campbell et al, 2006Campbell et al, , 2008Sousa et al, 2009). Recently, Eagleson et al (2011) reported a role for Met signaling in cortical interneuron development in vitro in a mouse model.…”

Mice with Impaired Met Tyrosine Kinase Signaling Demonstrate Characteristics Relevant to Autism

“…Chromosome 7q also contains the MET gene, located at 7q31 [59], as well as HGF, located at 7q21.1 [60]. Several MET variants have been shown to increase risk for ASDs [61][62][63][64][65][66]. One SNP in particular, rs1858830, has been found to be associated with the co-occurrence of autism with gastrointestinal conditions [63].…”