This web page was produced as an assignment for Genetics 564 at UW-Madison in Spring 2014.
PEX1 Mutant Phenotypes in Model Organisms
Model organism databases generally contain compilations of mutant phenotypes. In order to study any disease model, it is necessary to understand the phenotypes of these models. Listed below are the mutant phenotypes for model organisms typically used in research that have also been analyzed throughout this website as well as links to their respective genome databases.
Mus musculus (house mouse)
A knockout of Pex1 is publicly available, however, no mutant phenotypes are reported. A recently published study generated a knock-in mouse to re-capitulate human ZS. These mice have a slow-growth phenotype, bile acid defects, vision problems, and elevated levels of very long chain fatty acids [1].
Danio rerio (zebrafish)
There are only mutant lines of pex13, pex14, and pex19 available, all of which are involved in peroxisome biogenesis as well. Mutants of pex13 have fewer peroxisomes present in their liver and yolk cells at day four of development [2].
Drosophila melanogaster (fruit fly)
There are two mutant lines of pex1 publicly available. These mutants are lethal at the end of larval development, exhibit increased cell death, defective movement, defective feeding, abnormal body size, and nervous system defects. One mutant allele has been established as a model of ZS in two publications. This particular allele has been shown to have heightened levels of very long chain fatty acids and defects in spermatogenesis, in addition to the phenotypes described above [3,4].
Caenorhabditis elegans (roundworm)
A deletion allele for prx-1 is publicly available. This mutant is classified as being lethal or sterile [5].
Arabidopsis thaliana (thale cress)
There are various polymorphisms reported for PEX1, however, none have reported phenotypes.
Saccharomyces cerevisiae (yeast)
Analysis of PEX1 mutants has shown that these strains lack peroxisomes and cannot partake in peroxisomal transport. These strains also have a reduced resistance to various chemicals and have a heightened sensitivity to heat [6,7].
What is RNA Interference?
RNA interference (RNAi) is a biological process that knocks down the function of a gene. Using synthetic double-stranded RNA (dsRNA), phenotypes similar to those observed in mutants can be obtained, albeit less severe due to usual incomplete knockdown.
PEX1 RNAi Phenotypes in Model Organisms
Drosophila melanogaster (fruit fly)
There are two pex1 RNAi strains publicly available. One of the strains is reported to be viable [8].
Caenorhabditis elegans (roundworm)
Two different RNAi strains for prx-1 exhibit a slow growth phenotype [9].
Discussion
It is important to be mindful of the phenotypic differences across species as well as between phenotypes of mutant and RNAi lines. RNAi can often lead to an incomplete knockdown of the target gene, so phenotypically, these lines may be less severe than a complete loss of function mutant. By nature of its mechanism, RNAi can also have off-target effects.
Since pex-1 plays a role in peroxisome biogenesis, it is expected that the loss of this gene in models would yield a reduction in the number of peroxisomes present. Since this affects each cell in a very fundamental way, nearly eliminating the ability for it to process certain waste, the organismal phenotypes are expected to be severe.
Mouse phenotypes of the knock-in described above are consistent with those found in ZS patients. Hiebler, et al. state in their article that this mouse model could be used to identify new treatments for retinal degeneration in ZS patients as well as screening for small molecules that could affect the biochemical basis of the disease [1].
The fruit fly phenotypes described above are also consistent with human phenotypes. The fly is a very cost-effective model organism with fast generation times as large brood sizes. These factors make the fly a very good candidate organism for small molecule screening in pex1 mutants.
Since pex-1 plays a role in peroxisome biogenesis, it is expected that the loss of this gene in models would yield a reduction in the number of peroxisomes present. Since this affects each cell in a very fundamental way, nearly eliminating the ability for it to process certain waste, the organismal phenotypes are expected to be severe.
Mouse phenotypes of the knock-in described above are consistent with those found in ZS patients. Hiebler, et al. state in their article that this mouse model could be used to identify new treatments for retinal degeneration in ZS patients as well as screening for small molecules that could affect the biochemical basis of the disease [1].
The fruit fly phenotypes described above are also consistent with human phenotypes. The fly is a very cost-effective model organism with fast generation times as large brood sizes. These factors make the fly a very good candidate organism for small molecule screening in pex1 mutants.
[1] Hiebler S, Masuda T, Hacia J, Moser A, Faust P, Liu A, Chowdhury N, Huang N, Lauer A, Bennett J, Watkins P, Zack D, Braverman N, Raymond G, Steinberg S, The Pex1-G844D mouse: A model for mild human Zellweger spectrum disorder, Mol Genet Metab. 14 (2014) epub. PMID: 24503136
[2] Krysko O, Stevens M, Langenberg T, Fransen M, Espeel M, Baes M, Peroxisomes in zebrafish: distribution pattern and knockdown studies, Hitochem Cell Biol. 134 (2010) 39-51. PMID: 20556416
[3] Chen H, Liu Z, Huang X, Drosophila models of peroxisomal biogenesis disorder: peroxins are required for spermatogenesis and very-long-chain fatty acid metabolism, Human Mol Genet. 19 (2010) 494-505. PMID: 19933170
[4] Mast F, Li J, Virk M, Hughes S, Simmonds A, Rachubinski, A Drosophila model for the Zellweger spectrum of peroxisome biogenesis disorders, Dis Model Mech. 4 (2011) 659-672. PMID: 21669930
[5] Iino, Yuich, et al., eds. National Bioresource Project for the Experimental Animal "Nematode C. elegans." National BioResource Project, n.d. Web. 3 Mar. 2014. <http://www.shigen.nig.ac.jp/c.elegans/>.
[6] Erdmann R, et al., Saccharomyces Genome Database. Stanford University, n.d. Web. 3 Mar. 2014. <http://www.yeastgenome.org/>.
[7] Sinha H, David L, Pascon R, Clauder-Munster S, Krishnakumar S, Nguyen M, Shi G, Dean J, Davis R, Oefner P, McCusker J, Steinmetz L, Sequential elimination of major-effect contributors identifies additional quantitative trait loci conditioning high-temperature growth in yeast, Genetics 180 (2008) 1661-1670. PMID: 18780730
[8] Dietzl G, Chen D, Schnorrer F, Su K, Barinova Y, Fellner M, Gasser B, Kinsey K, Oppel S, Scheiblauer S, Couto A, Marra V, Keleman K, Dickson B, A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 488 (2007) 151-156. PMID: 18780730
[9] Simmer F, Moorman C, van der Linden A, Kuijk E, van den Berghe P, Kamath R, Fraser A, Ahringer J, Plasterk R, Genome-wide RNAi of C. elegans using the hypersensitive rrf-3 strain reveals novel gene functions, PLoS Biol 1 (2003) epub. PMID: 14551910
Image References
mouse: http://bioweb.uwlax.edu/bio203/s2009/smith_meg2/
zebrafish: http://www.watergardenersinternational.org/fish/danio_rerio.html
fly: http://en.wikipedia.org/wiki/File:Drosophila_melanogaster_-_front_(aka).jpg
worm: http://www.mun.ca/biology/scarr/4241_Devo_Germ_Celegans.html
thale cress: http://blogs.scientificamerican.com/observations/2010/01/01/good-mutations-stalking-evolution-through-genetic-mutation-in-plants/
yeast: http://earthemphasis.com/key-research-articles/a-new-biological-test-utilising-the-yeast-saccharomyces-cerevisiae-for-the-rapid-detection-of-toxic-substances-in-water/
[2] Krysko O, Stevens M, Langenberg T, Fransen M, Espeel M, Baes M, Peroxisomes in zebrafish: distribution pattern and knockdown studies, Hitochem Cell Biol. 134 (2010) 39-51. PMID: 20556416
[3] Chen H, Liu Z, Huang X, Drosophila models of peroxisomal biogenesis disorder: peroxins are required for spermatogenesis and very-long-chain fatty acid metabolism, Human Mol Genet. 19 (2010) 494-505. PMID: 19933170
[4] Mast F, Li J, Virk M, Hughes S, Simmonds A, Rachubinski, A Drosophila model for the Zellweger spectrum of peroxisome biogenesis disorders, Dis Model Mech. 4 (2011) 659-672. PMID: 21669930
[5] Iino, Yuich, et al., eds. National Bioresource Project for the Experimental Animal "Nematode C. elegans." National BioResource Project, n.d. Web. 3 Mar. 2014. <http://www.shigen.nig.ac.jp/c.elegans/>.
[6] Erdmann R, et al., Saccharomyces Genome Database. Stanford University, n.d. Web. 3 Mar. 2014. <http://www.yeastgenome.org/>.
[7] Sinha H, David L, Pascon R, Clauder-Munster S, Krishnakumar S, Nguyen M, Shi G, Dean J, Davis R, Oefner P, McCusker J, Steinmetz L, Sequential elimination of major-effect contributors identifies additional quantitative trait loci conditioning high-temperature growth in yeast, Genetics 180 (2008) 1661-1670. PMID: 18780730
[8] Dietzl G, Chen D, Schnorrer F, Su K, Barinova Y, Fellner M, Gasser B, Kinsey K, Oppel S, Scheiblauer S, Couto A, Marra V, Keleman K, Dickson B, A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 488 (2007) 151-156. PMID: 18780730
[9] Simmer F, Moorman C, van der Linden A, Kuijk E, van den Berghe P, Kamath R, Fraser A, Ahringer J, Plasterk R, Genome-wide RNAi of C. elegans using the hypersensitive rrf-3 strain reveals novel gene functions, PLoS Biol 1 (2003) epub. PMID: 14551910
Image References
mouse: http://bioweb.uwlax.edu/bio203/s2009/smith_meg2/
zebrafish: http://www.watergardenersinternational.org/fish/danio_rerio.html
fly: http://en.wikipedia.org/wiki/File:Drosophila_melanogaster_-_front_(aka).jpg
worm: http://www.mun.ca/biology/scarr/4241_Devo_Germ_Celegans.html
thale cress: http://blogs.scientificamerican.com/observations/2010/01/01/good-mutations-stalking-evolution-through-genetic-mutation-in-plants/
yeast: http://earthemphasis.com/key-research-articles/a-new-biological-test-utilising-the-yeast-saccharomyces-cerevisiae-for-the-rapid-detection-of-toxic-substances-in-water/