How mutated met gene and pollution with multiplicative interaction increase the chance of an individual developing ASD. Includes gene environment interaction as well

1. MET gene and its
interaction with
Autism
Hritika Sharma IBT SEM2
ASU2023010200079
GENETICS BSBT129
Submitted to Dr mohd Zeeshan Khan

2. WHAT IS AUTISM?
Autism spectrum disorder (ASD) is a
neurological and developmental disorder
that affects how people interact with
others, communicate, learn, and behave.
studies suggest that a person’s
genes can act together with aspects
of their environment to affect
development in ways that lead to
ASD.
The term "spectrum" in autism
spectrum disorder refers to the wide
range of symptoms and severity.

3. Symptoms and signs
children may develop normally for the first few months or
years of life, but then suddenly become withdrawn or
aggressive or lose language skills they've already acquired.
Signs usually are seen by age 2 years.
• Difficulty learning
• Lower or higher than average intelligence
• problems with social interaction and
communication skills
• Performs repetitive movements, such as rocking,
spinning or hand flapping
• Aversion to maintaining eye contact.

4. Factors that cause ASD
Autism spectrum disorder has no single known cause.
Both genetics and environment may play a role.
Genetics : Several different genes appear to be involved
in ASD. genetic changes (mutations) may increase the
risk of autism spectrum disorder. Still other genes may
affect brain development or the way that brain cells
communicate, or they may determine the severity of
symptoms.
Some genetic mutations seem to be inherited, while
others occur spontaneously.

5. Environmental factors: Researchers are currently
exploring whether factors such as viral infections,
medications or complications during pregnancy, or air
pollutants play a role in triggering autism spectrum
disorder.
Flowchart via MDPI

6. Genes linked with autism
Changes in over 1,000 genes have been reported to be associated
with ASD, but a large number of these associations have not been
confirmed.
The risk from gene variants combined with environmental risk
factors, such as parental age, birth complications, and others that
have not been identified, determine an individual's risk of
developing this complex condition.
Some genes in which rare mutations are associated with
ASD often with other signs and symptoms, are ADNP ,
ARID1B, ASH1L, CHD2, CHD8, DYRK1A, POGZ, SHANK3,
and SYNGAP1 and MET receptor tyrosine kinase gene

7. • ADNP : activity dependent neuroprotector homeobox provides instructions
for making a protein that helps control the activity (expression) of other
genes through a process called chromatin remodeling.
• ARID1B: gene provides instructions for making a protein that forms one
piece (subunit) of several different SWI/SNF protein complexes(regulate
gene activity).
• CHD2 and CHD8 gene: provides instructions for making a protein called
chromodomain DNA helicase protein 2.
• DYRK1A gene provides instructions for making an enzyme that is important
in the development of the nervous system.
• The POGZ gene provides instructions for making a protein that is found in
the cell nucleus.
• SHANK3 gene provides instructions for making a protein that is found in
many of the body's tissues but is most abundant in the brain.
• SYNGAP1 gene provides instructions for making a protein, called SynGAP,
that plays an important role in nerve cells in the brain.
• MET receptor tyrosine kinase (RTK) and its ligand hepatocyte growth factor
(HGF) MET RTK is involved in cancer cell growth/survival, motility/migration,
invasion/metastasis, and in angiogenesis.

8. Autism associated MET receptor tyrosine
kinase gene
The human MET gene imparts a replicated risk for autism
spectrum disorder (ASD), and is implicated in the structural
and functional integrity of brain. MET encodes a receptor
tyrosine kinase, which plays a pleiotropic role in
embryogenesis and modifies a large number of
neurodevelopmental events.
Dysregulated MET signaling may lead to pathological
changes in forebrain maturation and connectivity, and
thus contribute to the emergence of neurological
symptoms associated with ASD.

9. MET Gene in development of Autism
Spectrum Disorder
autism spectrum disorders are complex
neurodevelopmental disorders. The complex phenotypic
presentation of these disorders suggests that multiple
genetic and environmental factors contribute to risk, and
gene-environment interactions are widely believed to
underlie autism spectrum disorders.
Some Met gene mutations have also been implicated in
development of schizophrenia

10. Cont..
Independent studies carried out displayed the following outcom
(1) increased autism spectrum disorder risk among children exposed
to high levels of local near-roadway traffic-related air pollution and
regional particulate matter near the time of birth
(2) increased autism spectrum disorder risk among children with the C
allele of the MET gene promoter variant rs1858830, which is associated
with decreased expression of MET protein in brain and immune system
(3) decreased MET protein expression in brain and altered behavior
in offspring of mouse dams exposed during pregnancy to the
polycyclic aromatic hydrocarbon benzo(a)pyrene (a component of
traffic-related air pollution and particulate matter)

11. Air pollution and mutation in MET gene
Children of mothers living near a
freeway, and traffic-related
pollution, during the third
trimester of pregnancy were twice
as likely to develop ASD.
Children with a mutation in a gene
called MET, combined with high
levels of exposure to air pollution,
may have increased risk.
Air pollution – Researchers found early-life exposure
to air pollution may be a risk factor for autism.
Via ScienceDirect.com

12. Air pollution in ASD and MET gene mutations
In children, as in animals, prenatal polycyclic aromatic hydrocarbon
exposure has been associated with intelligence (IQ) deficits at age 5
years as well as with increased anxiety, depression, and inattention at
age 6–7.
A statistical test of multiplicative interaction identified a
statistically significant effect between NO2 and MET CC
genotype. The effects were observed to have been
increased when both the factors were present

13. Examination of joint pollution and gene effects suggest
that subjects with both the MET rs1858830 CC genotype
and high air pollutant exposure were at increased risk of
autism spectrum disorder
compared with subjects who had both the CG/GG
genotypes and lower air pollutant exposure.
Given that the MET CC genotype had no impact in the 75%
of the population with lower air pollutant exposures,
these data suggest a gene-environment interaction for
autism spectrum disorder based on MET genotype and
air pollution exposure.
Conclusions

14. Sources
Volk, Heather E et al. “Autism spectrum disorder: interaction of air pollution with
the MET receptor tyrosine kinase gene.” Epidemiology (Cambridge, Mass.) vol. 25,1
(2014): 44-7. doi:10.1097/EDE.0000000000000030
Peng, Y et al. “The autism-associated MET receptor tyrosine kinase engages
early neuronal growth mechanism and controls glutamatergic circuits
development in the forebrain.” Molecular psychiatry vol. 21,7 (2016): 925-35.
doi:10.1038/mp.2015.182
MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine
(US); [updated 2020 Jun 24]. Autism spectrum disorder;
Available from : https://medlineplus.gov/genetics/condition/autism-
spectrum-disorder/#causes

15. THANK YOU