MET Receptor Tyrosine Kinase as an Autism Genetic Risk Factor

Abstract

In this chapter, we will briefly discuss recent literature on the role of MET receptor tyrosine kinase (RTK) in brain development and how perturbation of MET signaling may alter normal neurodevelopmental outcomes. Recent human genetic studies have established MET as a risk factor for autism, and the molecular and cellular underpinnings of this genetic risk are only beginning to emerge from obscurity. Unlike many autism risk genes that encode synaptic proteins, the spatial and temporal expression pattern of MET RTK indicates this signaling system is ideally situated to regulate neuronal growth, functional maturation, and establishment of functional brain circuits, particularly in those brain structures involved in higher levels of cognition, social skills, and executive functions.

Immune mediators in the brain and peripheral tissues in autism spectrum disorder

“…Moreover, decreases in MET expression confer local hyperconnectivity, which is a putative hallmark of ASD pathophysiology 189 . Consistent with these results, reduced MET expression, as seen in ASD, alters key neurodevelopmental processes and is associated with structural and functional alterations in ASD 26 . Further investigation is needed to determine if targeting downstream MET signalling modulates circuit activity and ameliorates the impairments in socio-communicative function associated with decreased MET expression 31 .…”

“…One of the immune genes most associated with ASD is MET , which encodes hepatocyte growth factor receptor 26 . A MET variant that includes a common G-to-C single nucleotide polymorphism (SNP) in its promoter (the rs1858830 ‘C’ allele) is associated with decreased MET signalling in the temporal lobe and ASD 27–29 .…”

Annual Research Review: The role of the environment in the developmental psychopathology of autism spectrum condition

“…Thus, air pollution exposure may interfere with a signalling pathway that guides neurodevelopment, and this could be one mechanism that links TRAP and elevated ASC risk. Consistent with this idea is evidence that ASC risk from TRAP peaks in the third trimester and first year of life (Volk et al, 2013), at a time when the MET signalling pathway is thought to be especially influential on neuronal growth, then synaptogenesis and pruning, and then functional maturation and plasticity (Peng et al, 2013).…”

“…Volk et al (2014) recently reported data suggesting that exposure to TRAP exerts its effect on ASC risk via an interaction with a promoter variant of the MET receptor tyrosine kinase (MET) gene. The MET gene mediates a number of molecular signalling pathways during development, playing a role in the proliferation, differentiation and survival of cells in diverse tissues (Peng, Huentelman, Smith, & Qiu, 2013). It is crucial to the regulation of nervous system development, both in utero and after birth, and has been implicated in the development of some cases of ASC (Campbell, Li, Sutcliffe, Persico, & Levitt, 2008;Campbell et al, 2006Campbell et al, , 2007Sousa et al, 2009).…”

Disruption of MET Receptor Tyrosine Kinase, an Autism Risk Factor, Impairs Developmental Synaptic Plasticity in the Hippocampus

“…MET has emerged as a prominent risk gene for autism (Campbell et al, 2006;Campbell et al, 2007;Judson et al, 2011b;Peng et al, 2013;Eagleson et al, 2017). MET was initially established as a risk gene for autism based on a genome wide association study that reveals MET promoter rs1858830 "C" variant confers increased risk for ASD (Campbell et al, 2006).…”