The DOI matches its Crossref record; 38 of the 39 references it cites were found in a registry or an index.
A genetic variant that disrupts MET transcription is associated with autism
Open accessAbstract
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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“Furthermore, interactions with PAHs may involve loci encoding other proteins of the MET pathway, as these show secondary changes in gene expression [252], SERPINE1 and PLAUR gene variants are also associated with autism [254], and significant gene-gene interactions have been shown between MET and PLAUR [254].”
From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [252]
In the citing paper
“Furthermore, the C allele at rs1858830, located in the MET gene promoter, is significantly associated with autism and decreases MET transcription both in vitro and in postmortem brains [251, 252].”
From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [252]
In the citing paper
“Linkage studies by Campbell et al (2006), have found an association between ASD and a single SNP (rs1858830) in the promoter of MET.”
From The Role of the Immune System in Autism Spectrum Disorder (2017) · cites this paper as Campbell et al (2006)
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Metadata
- Authors
- Campbell, D. B., Sutcliffe, J. S., Ebert, P. J., Militerni, R., Bravaccio, C., Trillo, S., Elia, M., Schneider, C., Melmed, R., Sacco, R., Persico, A. M., & Levitt, P.
- Affiliations
- Vanderbilt University (US)
- University of Naples Federico II (IT)
- Associazione Anni Verdi ONLUS, 00148 Rome, Italy;
- Oasi Maria SS (IT)
- **Center for Autism Research and Education, Phoenix, AZ 85012;
- Southwest Autism Research & Resource Center (US)
- Università Campus Bio-Medico (IT)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-11-07
- Volume
- 103
- Issue
- 45
- Pages
- 16834-16839
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1838551
- OpenAlex
- W2131073955
- Cited by
- 401
- References
- 39
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 8 · 2023: 9 · 2022: 10 · 2021: 11 · 2020: 14 · 2019: 15 · 2018: 15 · 2017: 16 · 2016: 23 · 2015: 16 · 2014: 20 · 2013: 28 · 2012: 36
- FWCI
- 15.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Funders
- National Institute of Mental Health (R01MH061009, MH65299, MH 61009, MH 64547, R01MH064547, T32MH065215)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD015052)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- autism spectrum disorder, MET receptor tyrosine kinase, promoter polymorphism, genetic association, autism susceptibility, transcriptional regulation, multiplex families, chromosome 7q31, transcription factor binding, gene expression
- MeSH terms
- Alleles, Autistic Disorder, Base Sequence, Chromosome Mapping, Chromosomes, Human, Pair 7, DNA, Female, Genotype, Humans, Male, Promoter Regions, Genetic, Proto-Oncogene Proteins, Transcription Factors, Transcription, Genetic, Genetic Variation, Linkage Disequilibrium, Case-Control Studies, Receptors, Growth Factor, Proto-Oncogene Proteins c-met, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
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