Human Gene Module / Chromosome 7 / MET

METmet proto-oncogene (hepatocyte growth factor receptor)

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
12 / 34
Rare Variants / Common Variants
4 / 18
Aliases
MET, HGFR,  RCCP2, Oncogene MET,  met proto-oncogene
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association, Functional
Chromosome Band
7q31.2
Associated Disorders
-
Relevance to Autism

A number of studies have focused on the genetic association of the MET gene with autism. Positive associations have been found in the Caucasian, Japanese and Italian populations as well as in AGRE family cohorts from multiple studies. Interestingly, a positive association with MET and schizophrenia has also been found, but no association was found with PDD. In addition, biochemical studies have been performed that show a reduction in MET protein levels and general disruption of MET signaling in ASD patients.

Molecular Function

The encoded protein is the hepatocyte growth factor receptor with tyrosine-kinase activity. The primary single chain precursor protein is post-translationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor.

Reports related to MET (34 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Met receptor tyrosine kinase: enhanced signaling through adapter proteins. Furge KA , et al. (2000) No -
2 Highly Cited Coupling Met to specific pathways results in distinct developmental outcomes. Maina F , et al. (2001) No -
3 Recent Recommendation Disruption of interneuron development. Levitt P (2005) No -
4 Primary A genetic variant that disrupts MET transcription is associated with autism. Campbell DB , et al. (2006) Yes -
5 Recent Recommendation Hepatocyte growth factor-induced Ras activation requires ERM proteins linked to both CD44v6 and F-actin. Orian-Rousseau V , et al. (2006) No -
6 Recent Recommendation Disruption of cerebral cortex MET signaling in autism spectrum disorder. Campbell DB , et al. (2007) Yes -
7 Recent Recommendation Signalling by neurotrophins and hepatocyte growth factor regulates axon morphogenesis by differential beta-catenin phosphorylation. David MD , et al. (2008) No -
8 Positive Association MET and autism susceptibility: family and case-control studies. Sousa I , et al. (2008) Yes -
9 Recent Recommendation Dynamic gene and protein expression patterns of the autism-associated met receptor tyrosine kinase in the developing mouse forebrain. Judson MC , et al. (2009) No -
10 Positive Association Distinct genetic risk based on association of MET in families with co-occurring autism and gastrointestinal conditions. Campbell DB , et al. (2009) Yes -
11 Positive association Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder. Campbell DB , et al. (2009) Yes -
12 Positive Association Association of MET with social and communication phenotypes in individuals with autism spectrum disorder. Campbell DB , et al. (2009) Yes -
13 Recent Recommendation Disease-dependent reciprocal phosphorylation of serine and tyrosine residues of c-Met/HGF receptor contributes disease retardation of a transgenic ... Kadoyama K , et al. (2009) No -
14 Positive Association Further evidence that the rs1858830 C variant in the promoter region of the MET gene is associated with autistic disorder. Jackson PB , et al. (2009) Yes -
15 Recent Recommendation The autism susceptibility gene met regulates zebrafish cerebellar development and facial motor neuron migration. Elsen GE , et al. (2009) Yes -
16 Recent Recommendation Association of genetic variation in the MET proto-oncogene with schizophrenia and general cognitive ability. Burdick KE , et al. (2010) No -
17 Positive Association Further evidence for the role of MET in autism susceptibility. Thanseem I , et al. (2010) Yes -
18 Recent Recommendation Evidence of cell-nonautonomous changes in dendrite and dendritic spine morphology in the met-signaling-deficient mouse forebrain. Judson MC , et al. (2010) No -
19 Recent Recommendation Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase. Qiu S , et al. (2011) No -
20 Recent Recommendation Regulation of MET by FOXP2, genes implicated in higher cognitive dysfunction and autism risk. Mukamel Z , et al. (2011) No -
21 Recent Recommendation MET and AKT genetic influence on facial emotion perception. Lin MT , et al. (2012) No -
22 Recent Recommendation Autism-associated promoter variant in MET impacts functional and structural brain networks. Rudie JD , et al. (2012) Yes -
23 Recent recommendation Autism risk gene MET variation and cortical thickness in typically developing children and adolescents. Hedrick A , et al. (2012) No -
24 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Girirajan S , et al. (2013) Yes -
25 Recent Recommendation Synaptic and extrasynaptic location of the receptor tyrosine kinase met during postnatal development in the mouse neocortex and hippocampus. Eagleson KL , et al. (2013) No -
26 Recent Recommendation Transcriptional regulation of the MET receptor tyrosine kinase gene by MeCP2 and sex-specific expression in autism and Rett syndrome. Plummer JT , et al. (2013) No -
27 Recent Recommendation Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene. Volk HE , et al. (2013) No -
28 Recent recommendation A familial heterozygous null mutation of MET in autism spectrum disorder. Lambert N , et al. (2014) Yes -
29 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
30 Recent recommendation The autism-associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the f... Peng Y , et al. (2016) No -
31 Recent recommendation Hepatocyte Growth Factor Modulates MET Receptor Tyrosine Kinase and -Catenin Functional Interactions to Enhance Synapse Formation. Xie Z , et al. (2016) No -
32 Recent recommendation Autism spectrum disorders and autistic traits share genetics and biology. Bralten J , et al. (2017) No -
33 Highly Cited Uncoupling of Grb2 from the Met receptor in vivo reveals complex roles in muscle development. Maina F , et al. (1996) No -
34 Highly Cited Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Weidner KM , et al. (1996) No -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Unknown Not maternal Multiplex 24909855 Lambert N , et al. (2014)
c.3272G>A p.Cys1091Tyr missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.3751G>T p.Ala1251Ser missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants   (18)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.-207C>G;c.-200C>G;c.-283C>G G/C 2KB_upstream_variant, 5_prime_UTR_variant - - - 17053076 Campbell DB , et al. (2006)
c.-15+9171A>G;c.-8+9171A>G;c.-91+9171A>G G to A intron_variant - - - 19002214 Sousa I , et al. (2008)
c.-207C>G;c.-200C>G;c.-283C>G G/C 2KB_upstream_variant, 5_prime_UTR_variant - - - 19255034 Campbell DB , et al. (2009)
c.-207C>G;c.-200C>G;c.-283C>G C/G 2KB_upstream_variant, 5_prime_UTR_variant - - - 19360663 Campbell DB , et al. (2009)
c.-207C>G;c.-200C>G;c.-283C>G G/C 2KB_upstream_variant, 5_prime_UTR_variant - - - 19548256 Campbell DB , et al. (2009)
c.-207C>G;c.-200C>G;c.-283C>G G/C 2KB_upstream_variant, 5_prime_UTR_variant - - - 19681062 Jackson PB , et al. (2009)
c.1200+14187T>A;c.1257+14187T>A;c.-90-17197T>A A intron_variant - - - 20080979 Burdick KE , et al. (2010)
c.2583+2065T>C;c.2637+2065T>C;c.2694+2065T>C;c.1293+2065T>C;c.2640+2065T>C - intron_variant - - - 20080979 Burdick KE , et al. (2010)
c.3799-293G>A;c.3853-293G>A;c.3910-293G>A;c.2509-293G>A;c.3856-293G>A C intron_variant - - - 20080979 Burdick KE , et al. (2010)
c.*2262+71G>T;c.*2333G>T C 500B_downstream_variant - - - 20080979 Burdick KE , et al. (2010)
- T intergenic_variant - - - 20080979 Burdick KE , et al. (2010)
- A intergenic_variant - - - 20080979 Burdick KE , et al. (2010)
- T intergenic_variant - - - 20080979 Burdick KE , et al. (2010)
c.2583+2065T>C;c.2637+2065T>C;c.2694+2065T>C;c.1293+2065T>C;c.2640+2065T>C - intron_variant - - - 20080979 Burdick KE , et al. (2010)
c.3799-293G>A;c.3853-293G>A;c.3910-293G>A;c.2509-293G>A;c.3856-293G>A C intron_variant - - - 20080979 Burdick KE , et al. (2010)
- T intergenic_variant - - - 20080979 Burdick KE , et al. (2010)
c.-15+7295A>G;c.-8+7295A>G;c.-91+7295A>G A to G intron_variant - - - 20615438 Thanseem I , et al. (2010)
c.-15+7295A>G;c.-8+7295A>G;c.-91+7295A>G A to G intron_variant - - - 20615438 Thanseem I , et al. (2010)
SFARI Gene score
2

Strong Candidate

Under a linkage peak. At least 4 positive association studies (PMID: 17053076, 19255034, 19681062, 19360663), though not always the same findings (PMID: 19002214). One of the associated variants (rs1858830) is functional. Altered expression in autism brains vs controls (PMID: 17696172). Association with schizophrenia (PMID: 20080979).

2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

04-01-2017
2

Initial score established: 2

Description

Under a linkage peak. At least 4 positive association studies (PMID: 17053076, 19255034, 19681062, 19360663), though not always the same findings (PMID: 19002214). One of the associated variants (rs1858830) is functional. Altered expression in autism brains vs controls (PMID: 17696172). Association with schizophrenia (PMID: 20080979).

Reports Added
[Evidence of cell-nonautonomous changes in dendrite and dendritic spine morphology in the met-signaling-deficient mouse forebrain.2010] [Autism risk gene MET variation and cortical thickness in typically developing children and adolescents.2012] [MET and autism susceptibility: family and case-control studies.2008] [Association of genetic variation in the MET proto-oncogene with schizophrenia and general cognitive ability.2010] [Autism-associated promoter variant in MET impacts functional and structural brain networks.2012] [Uncoupling of Grb2 from the Met receptor in vivo reveals complex roles in muscle development.1996] [Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis.1996] [Distinct genetic risk based on association of MET in families with co-occurring autism and gastrointestinal conditions.2009] [Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder.2009] [Met receptor tyrosine kinase: enhanced signaling through adapter proteins.2000] [A familial heterozygous null mutation of MET in autism spectrum disorder.2014] [Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase.2011] [A genetic variant that disrupts MET transcription is associated with autism.2006] [Association of MET with social and communication phenotypes in individuals with autism spectrum disorder.2009] [Coupling Met to specific pathways results in distinct developmental outcomes.2001] [Further evidence for the role of MET in autism susceptibility.2010] [Hepatocyte growth factor-induced Ras activation requires ERM proteins linked to both CD44v6 and F-actin.2006] [Disruption of interneuron development.2005] [Transcriptional regulation of the MET receptor tyrosine kinase gene by MeCP2 and sex-specific expression in autism and Rett syndrome.2013] [Dynamic gene and protein expression patterns of the autism-associated met receptor tyrosine kinase in the developing mouse forebrain.2009] [Disruption of cerebral cortex MET signaling in autism spectrum disorder.2007] [Hepatocyte Growth Factor Modulates MET Receptor Tyrosine Kinase and -Catenin Functional Interactions to Enhance Synapse Formation.2016] [Further evidence that the rs1858830 C variant in the promoter region of the MET gene is associated with autistic disorder.2009] [The autism susceptibility gene met regulates zebrafish cerebellar development and facial motor neuron migration.2009] [Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene.2013] [Regulation of MET by FOXP2, genes implicated in higher cognitive dysfunction and autism risk.2011] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Synaptic and extrasynaptic location of the receptor tyrosine kinase met during postnatal development in the mouse neocortex and hippocampus.2013] [The autism-associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the f...2016] [Autism spectrum disorders and autistic traits share genetics and biology.2017] [MET and AKT genetic influence on facial emotion perception.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Signalling by neurotrophins and hepatocyte growth factor regulates axon morphogenesis by differential beta-catenin phosphorylation.2008] [Disease-dependent reciprocal phosphorylation of serine and tyrosine residues of c-Met/HGF receptor contributes disease retardation of a transgenic ...2009]
CNVs associated with MET(1 CNVs)
7q31.2 8 Deletion-Duplication 16  /  98
Animal Models associated with MET(8 Models)
MET_1_KO_HM Genetic
MET_2_KO_HT Genetic
MET_3_KI_Y1349F Genetic
MET_4_KI_N1358H Genetic
MET_5_CN_KO_HM Genetic
MET_6_CN_KO_HM Genetic
MET_6_GRB2_HM Genetic
MET_7_CN_KO_HT Genetic
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CEACAM21 Carcinoembryonic antigen-related cell adhesion molecule 21 Human Protein Binding 90273 Q3KPI0-2
Elmod1 ELMO/CED-12 domain containing 1 Mouse Protein Binding 270162 Q3V1U8
Eng ROBO1 Human Protein Binding 2022 P17813
Erc2 ELKS/RAB6-interacting/CAST family member 2 Mouse Protein Binding 238988 Q6PH08
HGF hepatocyte growth factor (hepapoietin A; scatter factor) Human Protein Binding 3082 P14210
INPP5D inositol polyphosphate-5-phosphatase D Rat Protein Binding 54259 P97573
ITGB4 integrin, beta 4 Human Protein Modification 3691 P16144
Klf8 Kruppel-like factor 8 Zebrafish Direct Regulation 562805 A0S0R1
MACC1 metastasis associated in colon cancer 1 Human RNA Binding 346389 Q6ZN28
miR-148a microRNA 148a Mouse RNA Binding 387166 N/A
miR-340 microRNA 340 Mouse RNA Binding 723845 N/A
miR-34b microRNA 34b Mouse RNA Binding 723849 N/A
miR-34c microRNA 34c Human RNA Binding 407042 N/A
miR185 microRNA 185 Human RNA Binding 406961 N/A
MUC20 mucin 20, cell surface associated Human Protein Binding 200958 Q8N307
Pcdhgc5 protocadherin gamma subfamily C, 5 Mouse Protein Binding 93708 Q91XW9
Pea3 ETS translocation variant 4 Mouse Direct Regulation 18612 P28322
PTPRB protein tyrosine phosphatase, receptor type, B Human Protein Modification 5787 P23467
Rack1 receptor for activated C kinase 1 Mouse Protein Binding 14694 P68040
SCGB1D1 Secretoglobin family 1D member 1 Human Protein Binding 10648 O95968
Scn2a1 sodium channel, voltage-gated, type II, alpha 1 Mouse Protein Binding 110876 B1AWN6
Snx20 sorting nexin 20 Mouse Protein Binding 71607 Q9D2Y5
SPSB1 splA/ryanodine receptor domain and SOCS box containing 1 Human Protein Binding 80176 Q96BD6
SPSB4 splA/ryanodine receptor domain and SOCS box containing 4 Human Protein Binding 92369 Q96A44
Tenm4 teneurin transmembrane protein 4 Mouse Protein Binding 23966 Q3UHK6
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