Further evidence for the role of MET in autism susceptibility
Introduction
Autism is a prevalent neurodevelopmental disorder defined by profound impairments in the emergence of social behaviors and communication, traditionally diagnosed by the age of 3 years. Restricted interests and repetitive and stereotyped behaviors are also prominent features of the disorder (Lord et al., 2000). Although, once considered to be relatively rare, recent estimates show a prevalence of 1 in 500 for a strict diagnosis and 1 in 150 using broader diagnostic criteria (Kuehn, 2007). Though this alarming increase in prevalence can be attributed partly to the broadening of diagnostic criteria and improvement of diagnostic capacity (Steyaert and De la Marche, 2008), it emphasizes the pressing urgency for determining the etiology of autism, which remains still largely cryptic.
An armamentarium of techniques and tools developed in the last decade provides several lines of evidence that support the role of genetic factors in the etiology of autism. Defining mutations and structural variations in any of several genes increases the disease risk in many reports (Losh et al., 2008). Family and twin studies have generated overwhelming evidence about the high heritability of autism spectrum disorders. Gene association studies, whole genome linkage studies and genome wide techniques to identify copy number variations showed genetic causes for about 10–20% of ASD cases, at present (Abrahams and Geschwind, 2008). However, none of these known causes individually account for more than 1–2% of the cases, depicting the genetic heterogeneity of the disorder, which made identification of a common genetic variant a near impossible task.
A promoter functional SNP, rs1858830, that disrupts the transcription of the MET receptor tyrosine kinase (MET) gene, which is located in a common autism linkage region, chromosome 7q31, has been reported to be strongly associated with autism in a family based association study consisting of 204 autism families of Caucasian origin (Campbell et al., 2006). The finding was replicated in a sample of 539 autism families (combined p = 5 × 10−6). Case–control comparisons found significant overrepresentation of the ‘C’ allele in autism with a relative risk of 2.27. It was found that the ‘C’ variant causes an altered binding of specific transcription factor complexes that result in a two-fold decrease in MET promoter activity (Campbell et al., 2006). Signaling mediated by MET and its single known ligand, hepatocyte growth factor (HGF), has been implicated in a variety of physiological, developmental and repair processes (Birchmeier et al., 2003).
The importance of MET signaling in the pathophysiology of autism has begun to be recognized. The findings of Campbell et al. (2006) represent the first robust connection of a functional genetic variant with idiopathic autism and replication studies in different populations are warranted (State, 2006). Previously we reported significantly reduced levels of HGF in the serum samples of Japanese autistic patients compared to age-matched controls (Sugihara et al., 2007). Here, we performed a trio-based study to examine the association of MET with autism in Japanese subjects and tried to replicate our findings in Caucasian trio families.
Section snippets
Subjects
The subjects included 126 children with ASD [diagnosis: 118 autism, 8 pervasive developmental disorder not otherwise specified; sex: 107 males, 19 females; age: 10.49 ± 4.75 (mean ± SD); IQ: 82.06 ± 26.6] and their parents (total 378 individuals). The purpose of the study was fully explained to the participants, and written informed consent was obtained. The study was approved by the ethics committees of the participating institutes.
Based on interviews and available information including the hospital
Single SNP TDT
Mendelian inheritance inconsistencies were not observed for any of the SNPs. For each SNP, >99% of the genotypes were scored; none of the SNPs showed deviation from HWE.
The results of TDT analysis are shown in Table 1. rs38841 showed nominal association with autism (p = 0.044; OR = 1.61; 95% CI 1.01–2.58). The major allele (A) of rs38841 showed over-transmission (52.04%). However, this does not withstand the multiple testing correction. The promoter functional variant rs1858830 which showed strong
Discussion
In this study, we examined the association of the HGF receptor MET with autism in the Japanese population. Though limited by small sample size, our study is to the best of our knowledge, the first replication study on any non-Caucasian population involving the association of MET with autism since Campbell et al. (2006) reported a robust association for a promoter functional variant (rs1858830) in Caucasian autism samples. However, in our trio-based study, we could not find any association for
Acknowledgments
We gratefully acknowledge the support of the Autism Genetic Resource Exchange program (www.agre.org). This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. We thank Prof. Pat Levitt for his advice.
References (28)
- et al.
Hepatocyte growth factor as an enhancer of NMDA currents and synaptic plasticity in the hippocampus
Neuroscience
(2004) - et al.
Pioglitazone as a therapeutic agent in autistic spectrum disorder
Med. Hypotheses
(2007) - et al.
The autism genetic resource exchange: a resource for the study of autism and related neuropsychiatric conditions
Am. J. Hum. Genet.
(2001) - et al.
Autism spectrum disorders: developmental disconnection syndromes
Curr. Opin. Neurobiol.
(2007) - et al.
Activation of PI3K-Akt-GSK3beta pathway mediates hepatocyte growth factor inhibition of RANTES expression in renal tubular epithelial cells
Biochem. Biophys. Res. Commun.
(2005) - et al.
Regulation of neocortical interneuron development and the implications for neurodevelopmental disorders
Trends Neurosci.
(2004) - et al.
Autism spectrum disorders
Neuron
(2000) - et al.
GSK3beta-mediated phosphorylation of the microtubule-associated protein 2C (MAP2C) prevents microtubule bundling
Eur. J. Cell Biol.
(2000) - et al.
Decreased serum levels of hepatocyte growth factor in male adults with high-functioning autism
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2007) - et al.
Advances in autism genetics: on the threshold of a new neurobiology
Nat. Rev. Genet.
(2008)
Diagnostic and Statistical Manual of Mental Disorders
MET, metastasis, motility and more
Nat. Rev. Mol. Cell Biol.
A genetic variant that disrupts MET transcription is associated with autism
Proc. Natl. Acad. Sci. U.S.A.
Disruption of cerebral cortex MET signaling in autism spectrum disorder
Ann. Neurol.
Cited by (44)
The Pleiotropic MET Receptor Network: Circuit Development and the Neural-Medical Interface of Autism
2017, Biological PsychiatryCitation Excerpt :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). However, there are two important facts to emphasize in our and others’ genetic findings.
Autoimmunity, Autoantibodies, and Autism Spectrum Disorder
2017, Biological PsychiatryReceptor Tyrosine Kinase MET Interactome and Neurodevelopmental Disorder Partners at the Developing Synapse
2016, Biological PsychiatryImmune Dysfunction in Autism Spectrum Disorder
2016, Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual DisabilityUrine proteome analysis to evaluate protein biomarkers in children with autism
2015, Clinica Chimica ActaCitation Excerpt :The human MET gene encodes MET receptor tyrosine kinase (MET RTK) which emerges as a prominent autism risk factor. MET signaling mediates invasive growth and neurite extension and contributes to brain development [30]. MET transcript and protein expression are found to be decreased in individuals with autism spectrum disorder (ASD) compared to matched controls.
Common Genetic Variants in Autism Spectrum Disorders
2013, The Neuroscience of Autism Spectrum Disorders
- 1
The first three authors contributed equally to this work.