Future Directions

Much remains to be learned about the genetic basis of vitiligo. While it is known that vitiligo is a condition in which the body attacks its own melanocytes, the exact genetic aberrations of this autoimmune response remain at large. Population studies in which the genomes of vitiligo vs. non-vitiligo patients were examined have revealed that single-nucleotide polymorphisms (SNPs) exist within the NLRP1 gene. 

NLRP1 is associated with a caspase cascade event, triggering cell death. It is unknown, but suspected, that these polymorphisms found in vitiligo patients are causing overreactive immune responses. Future studies will be necessary to elucidate the roles of SNPs within the NRLP1 gene. 


Proposed Research
HypothesisMutations (SNPs) in the NLRP1genecause NLRP1 to remain in a constitutively active conformation, even in the absence of MDP. This conformation allows continuous formation of the NLRP1 inflammasome, resulting in chronic apoptosis of melanocytes.


Experimental Design:
Clone DNA extracted from vitiligomelanocytes
Look for SNPs seen in vitiligo studies
e.g. Lys to His at 155
Insert sequence into vector
Generate mouse ES cells with vector insertion and inject into mouse blastocyst
Look for vitiligo phenotype in transgenic mouse

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Y2H - Look to see if NLRP1 is bound to caspases even in the absence of MDP.
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Future Directions: Correlation to Causation

While the above experiments show that mutant NLRP1 is correlated with an active conformation of the protein, future experiments need to be done that show that SNPs within the gene are causative. 

Anti-apoptotic proteins Bcl-2 and Bcl-XL inhibit ATP binding required by NLRP1 oligomerization (active conformation) 
Hypothesis: SNPs in vitiligo  NLRP1 gene prevent Bcl-2 and Bcl-XL from binding NLRP1 
Experiment: Look at NLRP1 binding of Bcl-2 and Bcl-XL in WT/TG models


It also may be helpful to look at the amino acid modification on SNPs:

¤Ubiquination 
¤Glycosylation 
¤Methylation 
¤Phosphorylation 
¤SUMOylation
This Web site was created as an assignment for Genetics 677 at UW-Madison, Spring 2010.


Sarah Hamilton. May 17, 2010.