Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder

Autism Research - Tập 1 Số 3 - Trang 159-168 - 2008
Jerry L. Campbell1,2,3, Chun Li4, James S. Sutcliffe5,2, Antonio M. Persico6, Pat Levitt1,2,3
1Department of Pharmacology
2Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee
3Vanderbilt University, Nashville, Tennessee
4Department of Biostatistics, Vanderbilt University, Nashville, Tennessee
5Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
6Laboratory of Molecular Psychiatry and Neurogenetics, University Campus Bio-Medico, Rome, Italy (A.M.P.), I.R.C.C.S. “Fondazione S. Lucia”, Rome, Italy

Tóm tắt

AbstractA functional promoter variant of the gene encoding the MET receptor tyrosine kinase alters SP1 and SUB1 transcription factor binding, and is associated with autism spectrum disorder (ASD). Recent analyses of postmortem cerebral cortex from ASD patients revealed altered expression of MET protein and three transcripts encoding proteins that regulate MET signaling, hepatocyte growth factor (HGF), urokinase plasminogen activator receptor (PLAUR) and plasminogen activator inhibitor‐1 (SERPINE1). To address potential risk conferred by multiple genes in the MET signaling pathway, we screened all exons and 5′ promoter regions for variants in the five genes encoding proteins that regulate MET expression and activity. Identified variants were genotyped in 664 families (2,712 individuals including 1,228 with ASD) and 312 unrelated controls. Replicating our initial findings, family‐based association test (FBAT) analyses demonstrated that the MET promoter variant rs1858830 C allele was associated with ASD in 101 new families (P=0.033). Two other genes in the MET signaling pathway also may confer risk. A haplotype of the SERPINE1 gene exhibited significant association. In addition, the PLAUR promoter variant rs344781 T allele was associated with ASD by both FBAT (P=0.006) and case–control analyses (P=0.007). The PLAUR promoter rs344781 relative risk was 1.93 (95% confidence interval [CI]: 1.12–3.31) for genotype TT and 2.42 (95% CI: 1.38–4.25) for genotype CT compared to genotype CC. Gene–gene interaction analyses suggested a significant interaction between MET and PLAUR. These data further support our hypothesis that genetic susceptibility impacting multiple components of the MET signaling pathway contributes to ASD risk.

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Tài liệu tham khảo

10.1055/s-2006-926584

10.1136/jmg.2004.024646

10.1002/ana.21180

10.1002/ana.21180

Centers for Disease Control and Prevention, 2007, Prevalence of autism spectrum disorders–autism and developmental disabilities monitoring network, 14 sites, United States, 2002, Morbidity and Mortality Weekly Report: Surveillance Summaries, 56, 12

10.1002/gepi.10307

10.1074/jbc.M413954200

10.1002/cne.20647

10.1016/j.conb.2007.01.009

10.1016/j.biopsych.2006.06.020

10.1016/j.neuro.2006.03.017

10.1002/ajmg.a.31619

10.1038/sj.ejhg.5200625

10.1002/gepi.10295

10.1038/nature04226

10.1159/000103512

10.1159/000084164

10.1111/j.1528-1167.2005.00305.x

10.1111/j.1528-1167.2005.00305.x

10.1371/journal.pbio.0050035

10.1002/j.1460-2075.1992.tb05315.x

10.1016/j.tins.2006.05.010

10.1016/S0896-6273(01)00264-1

10.1016/S0896-6273(01)00264-1

10.1016/j.biopsych.2006.11.010

10.1074/jbc.M008220200

10.1097/00004703-200604002-00011

10.1016/S0002-9440(10)63675-9

10.1038/sj.ejhg.5201644

10.1177/153537020322800601

Xue W., 1997, Urokinase‐type plasminogen activator receptors associate with beta1 and beta3 integrins of fibrosarcoma cells: dependence on extracellular matrix components, Cancer Research, 57, 1682

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Autism Research

Tập 1 Số 3

159-168

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