Myopia and LEPREL1

Christen Geyer

getmascular.blogspot.com

What is myopia?

LEPREL1 gene/protein
Future directions

www.funnyfidos.com

What is Myopia?

NEARSIGHTEDNESS
http://www.youtube.com/watch?feature=player_embedded&v=J0_LLx1YF0A

What is Myopia?

themeanings.com

www.wpclipart.com

AND ITS ONLY

www.wpclipart.com

Diagnosis and Treatment

Standard eye exam

losangeleseyeexam.com

Diagnosis and Treatment

Standard eye exam

losangeleseyeexam.com

Glasses/Contact Lenses

Diagnosis and Treatment

Standard eye exam

losangeleseyeexam.com

LASIK

Glasses/Contact Lenses

www.pinnacleeyecenter.com

Diagnosis and Treatment

Standard eye exam

losangeleseyeexam.com

LASIK

Glasses/Contact Lenses
Orthokaratology

www.pinnacleeyecenter.com

www.orthokdoctors.com

What is myopia? LEPREL1 gene/protein

Future directions

www.funnyfidos.com

LEPREL 1- A Genetic Link to Myopia

LEPREL1 Fe2OG

Leprel1/P3H2

www.uscnk.com

LEPREL 1- A Genetic Link to Myopia

Glycine > Valine Fe2OG LEPREL1

Leprel1/P3H2

www.uscnk.com

Leprel1 and Collagen Metabolism

http://www.rcsb.org/pdb/101/motm.do?momID=4

Leprel1

80%
www.sciencedirect.com

What is myopia?

LEPREL1 gene/protein
Future directions

www.funnyfidos.com

Hypothesis: misfolded collagen can be rescued

LEPREL1 Fe2OG

+?

www.sciencedirect.com

Leprel1 is well conserved in vertebrates

length % identity

Leprel1

human chimpanzee rat

Fe2OG

708 527 703 99%

P3H2 P3H2
P3H2 HIF PH Y73F8A.26 Tma17p

93% 62%
33% 34% 33%

zebrafish fruit fly

roundworm yeast

678
325 476 150

Why zebrafish?
Clarity of early embryo Relatively large eye
Easy morphological screening

Mature collagen architecture ~30 days post-fertilization

www.renalgenes.org

Fadool, James, et al (2008)

Is an interactor also responsible for phenotype?

Prolyl 3hydroxylase Accelerates protein folding

http://string-db.org

Disulfide bond rearrangement

What are the expression levels of Leprel1 interactors?

PPIB- peptidyl prolyl isomerase B (cyclophilin B) LEPRE1- leprecan 1

1. Protein microarray of interactors

Wild Type PPIB LEPRE1 Leprel1 Mutant PPIB LEPRE1 PPIB knockout PPIB LEPRE1 LEPRE1 knockout PPIB LEPRE1

Expression: Low Normal High

Is there a compound that can modulate PPIB activity?

2. Chemical screen

PPIB modulator

Rescued phenotype?
Stockwell, Brent. Nature (2004)

Can we substitute another prolyl 3-hydroxylase?

LEPRE1

LEPREL1

P4Hc = Fe2OG

Can LEPRE1 substitute for LEPREL1?

3. Supplement LEPRE1 +/- PPIB modulator
Adult
zf-health.org

4. Test with Microarray

Expression: High Wild Type Leprel1 Mutant PPIB knockout

PPIB

LEPRE1

PPIB

LEPRE1

PPIB

LEPRE1

Normal
Low

PPIB modulator + LEPRE1

beinghealthyblog.blogspot.com

Even more
Examine autosomal dominant collagen types
Comparative studies in organisms that dont have eyes

See how Vitamin C (cofactor) affects Leprel1 function

www.collagensupplements.biz

Questions?

1. 2.

3. 4. 5.
6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Fredrick, Douglas. 18 May 2002. Myopia. Clinical Review. BMJ 2002; 324 doi:http://dx.doi.org/10.1136/bmj.324.7347.1195 American Associates, Ben-Gurion University of the Negev. 2 Sep 2011. Researchers identify gene that leads to myopia (nearsightedness). ScienceDaily. Retrieved 24 Jan 2013 from <http://www.sciencedaily.com/releases/2011 /09/110901135018.htm> http://www.allaboutvision.com/eye-exam/expect.htm http://www.allaboutvision.com/conditions/myopia.htm Kirschbaum OD, Stephanie, Curry, S.R., Buckley, Maggie. 19 Aug. 2007. "Ehlers-Danlos SyndromeThe Role of Collagen in the Eye." Retrieved 4 Feb. 2013 from <http://www.newtonsonline.net/histories/ehlers%20danlos%20eyes.pdf > http://www.uscnk.com/directory/Leprecan-Like-Protein-1(LEPREL1)-7747.htm http://www.newtons-online.net/histories/ehlers%20danlos%20eyes.pdf http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169819/ Homologene. http://www.ncbi.nlm.nih.gov/homologene Blast. http://blast.ncbi.nlm.nih.gov/Blast.cgi ClustalW2. http://www.ebi.ac.uk/Tools/services/rest/clustalw2/result/clustalw2-I20130222044611-0089-45687487-oy/aln-clustalw Pfam. http://pfam.sanger.ac.uk/ SMART. http://smart.embl-heidelberg.de/ Prosite. http://prosite.expasy.org/ Fe(2+) 2-oxoglutarate dioxygenase domain profile. http://prosite.expasy.org/cgibin/prosite/nicedoc.pl?PS51471 http://www.geneontology.org/

References

17. Mordechai, Shikma, Libe Gradstein, Annika Pasanen, Rivka Ofir, Khalil El Amour, Jaime Levy, Nadav Belfair, Tova Lifshitz, Sara Joshua, Ginat Narkis, Khalil Elbedour, Johanna Myllyharju, and Ohad S. Birk. "High Myopia Caused by a Mutation in LEPREL1, Encoding Prolyl 3-Hydroxylase 2." The American Journal of Human Genetics 89.3 (2011): 438-45. Web.