The Missing Link

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The Missing Link

• Deletions in chromosomes 1 and 15 are associated
  with schizophrenia

Kate Watkins October 22, 2009
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Schizophrenia

• Neural-developmental disorder that affects 1.1
  of the population each year
• Men late teens, early twenties
• Women twenties and thirties
• Symptoms
• -hallucinations or delusions
• -disordered thoughts
• -social withdrawl or paranoia
• -movement disorders

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Increased dopamine seen in schizophrenics
Specific pathway affected in schizophrenia is
known to be involved in modulating behavioral
responses to stimuli that activate feelings of
reward and re-enforcement through dopamine
response
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Very few genes linked with schizophrenia
Disrupted in schizophrenia 1 (DISC1) has been
genetically linked to schizophrenia and bipolar
disorder DISC1 regulates the proliferation of
embryonic and adult neural progenitor cells
through the GSK3/ß-catenin pathway
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GSK3 and ß-catenin are involved in Wnt signaling
pathway of gene regulation
http//en.wikipedia.org/wiki/FileSignal_transduct
ion_v1.png
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Recurrent microdeletions at 1q21.1 and 15q11.2
are associated with schizophrenia
Hreinn Stefansson PhD, et al
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SNPs vs CNV
Schizophrenia is associated with reduced
reproductive capacity -negative selective
pressure on causal variations -common variants
will be weeded out Rare variants and multiple
locations may account for many cases -too low
frequency to do SNP microarray analysis -copy
number variation (CNV) tested by DNA dosage
analysis
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Study progression

• Tested 6 european populations for CNV association
  with schizophrenia (9878 transmissions)
• Follow up testing done in 5 replications samples

IDd 51 deletions and 15 duplications
3 deletions were associated with schizophrenia
(1q21, 15q11.2, 15q13.3) none of the
duplications were associated
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Flourescence in situ Hybridization (FISH)
A microscopic technique to visualize specific
areas of chromosomes
Nuclear Health Center
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FISH continued
Genome.gov
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CNV visualized with FISH
RED probe control region GREEN probe PRK gene
on chromosome 1 (1q21)
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Deletion at 1q21.1 spans 1.35 MB
Over 100 SNPs are deleted Several genes are
deleted connexin 50/GJA8
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Connexin 50 (GJA8) associates with schizophrenia
Journal of Medical Genetics 200744532-536
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Connexin 50 (GJA8) associates with schizophrenia
http//mouse.brain-map.org/brain/Gja8.html?ispopup
true
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Connexins are Gap Junction Proteins

• Intercellular communication
• Transport of ions and small signaling
  molecule
• Tissue specific expression

• Disruption of Connexins
• Interfere with cellular communication
• Cellular degeneration or apoptosis

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Deletion at 15q11.2 spans 470 kb
Deleted genes include cytoplasmic FMRP
interacting protein 1 (CYFIP1)
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CYFIP1 is required for neuronal development
GREEN anti-FAS II recognizes synapses RED
anti-CYFIP localizes to neuromuscular junction
(NMJ) YELLOW overlapping regions in
neuromuscular junction (NMJ) NMJ is junction of
axon terminal of a motorneuron with the motor end
plate Responsible for muscle contractions
Neuron 200338887-898
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CYFIP1 is required for neuronal development
Labeled muscle 4 synaptic terminals CYFIP
deletion causes undergrowth, and budding of
axons similar to block in synapse differentiation
Neuron 200338887-898
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Two genes identified are involved in neuronal
signaling and development
Connexin 50/Gap junction protein 8
(GPA8) Intercellular communiction Ion
transport Transportation of small signaling
molecules
Cytoplasmic FMRP-interacting protein 1
(CYFIP1) Synaptic differentiation NMJ
development Also shown to be associated with
Prader-Willi syndrome and Angelman syndrome
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Conclusions
Identified 2 regions of CNV with large
deletions Deleted regions contain many genes
that may be involved in schizophrenia More
biological studies are required to test the
involvement of these genes