Lesch-Nyhan Syndrome (LNS) and the HPRT1 Gene Billy

Lesch-Nyhan Syndrome (LNS) and the HPRT1 Gene Billy

Lesch-Nyhan Syndrome (LNS) and the HPRT1 Gene Billy Maes What is Lesch-Nyhan Syndrome? Gouty arthritis Kidney stones Loss of motor control Cognitive problems Self-mutilation What is Lesch-Nyhan

Syndrome? https://www.youtube.com/watch?v=1U6LDpF_LFE What causes Lesch-Nyhan Syndrome? Excess uric acid gout and kidney stones **Unknown mechanism neurological symptoms >300 mutations in HPRT1 are known to cause LNS

Point mutations Loss-of-function mutations Change in size, shape HPRT protein Human How well conserved is HPRT? 218 aa % Identity Phosphoribosyl transferase domain Mouse 218

97% Chicken 218 91% Zebrafish 218 91% Roundworm

214 49% Arabidopsis 188 31% What are HPRT1s GO terms? Biological Processes Neuron development and differentiation

Molecular Functions Nucleotide binding Purine Salvage Pathway Phosphribosyltransferase activity Dopamine metabolism Magnesium ion binding Dendrite morphogenesis Locomotory behavior Cellular

Components Cytoplasm Dopamine Pharmacological Rat Model Reduce brain dopamine in neonatal rats using neurotoxin 6-OHDA Pleasure Reward motivation Motor function Compulsive behavior **LNS phenotypes may be caused by abnormal brain development, induced by low dopamine levels neonatally

Gap in Knowledge Hypothesis and Primary Goal Hypothesis: HPRT1 regulates the development of the dopaminergic system, important for normal cognition and behavior, through protein interactions in the brain. Primary Goal: Determine the genomic and proteomic changes that contribute to LNS neurological dysfunction as a result of loss-offunction mutations in HPRT1. Zebrafish: A Model Organism for LNS

91% identity to human HPRT Contains many of the same brain structures and developmental features as humans Cheap and easy to grow on a large-scale Short, rapid development Dopamine is important in brain function and development, as in humans Transparent development Specific Aim #1: Identify proteins that interact with HPRT Affinity

purification- mass spectrometry (AP-MS) STRING database Determine function of HPRT interaction partners Specific Aim #1: Identify proteins that interact with HPRT **SQSTM1 activates NF-KB (synaptic plasticity & dendrite growth), NGF (nerve growth), and titin/TTN (linked to movement disorders) Specific Aim #2: Determine which

proteins are over- or under-expressed in HPRT1-mutant zebrafish Quantitative mass spectrometry: Compare protein levels in wild-type and HPRT-mutant zebrafish **Hypothesis: SQSTM1 decreases in HPRT mutants Specific Aim #3: Determine how gene expression levels change during neuronal brain development in HPRT-mutant zebrafish HPRT-mutant DNA microarray of brain cells at each stage of development

**Indicate when mutations in HPRT1 alter neuronal gene function, indicating how brain development may be altered Conclusions Directions These aims are expected to Future indicate how gene expression and protein interactions change as a of HPRT mutations. Alter levels of SQSTM1 and other Gain insight into the proteins that interact with HPRT1.

mechanisms that lead to the Observe if neurological or behavioral neuronal-behavioral phenotypes LNS phenotypes appear in mice. of LNS. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

13. 14. 15. 16. 17. Image URLs and References http://www.gnet.org/wp-content/uploads/explained-got-disease.jpg http://www.keystonekidney.com/images/about-kidney-stones.gif http://simple-health-secrets.com/wp-content/uploads/2013/06/Lesch-Nyhan-Syndrome-4.jpg http://medicalpictures.net/wp-content/uploads/2010/10/Lesch-Nyhan-Syndrome-pictures-3.jpg http://www.ojrd.com/content/2/1/48/figure/F1 http://4.bp.blogspot.com/-IZrB3OKIHH8/Uo7dqy5kLSI/AAAAAAAAABA/2ahaXRkqelg/s72-c/leshnyhan.jpg http://www.movementdisorders.org/MDS-Files1/Journals/Images/CPJ-Volume-1-Issue-3/mdc312040-fig-0001.png http://www.cdb.riken.jp/jp/04_news/annual_reports/2006/WebHelp/common/lab1_07hlfig2.htm

http://drrajivdesaimd.com/wp-content/uploads/2013/06/dopamine-pathways.jpg http://www.stats.ox.ac.uk/~hamer/images/complex.png http://www.posturologiaclinica.net/img/rx_cranio_brain_02.jpg http://www.nature.com/nrm/journal/v8/n8/images/nrm2208-f1.jpg http://transforming-science.com/wp-content/uploads/2013/12/Zebrafish-aquarium.-010.jpg http://kimgen677s10.weebly.com/uploads/3/6/1/8/3618941/290277.jpg?325 http://upload.wikimedia.org/wikipedia/en/thumb/c/c8/Microarray-schema.jpg/220px-Microarray-schema.jpg https://denisezannino.files.wordpress.com/2013/07/zebrafish-kimmel.jpg http://cdn.superbwallpapers.com/wallpapers/3d/mechanism-15796-1920x1200.jpg 18. Torres RJ and Puig JG. (2007). Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome. Orphanet Journal of Rare Diseases, 2, 48. doi:10.1186/17501172-2-48 19. Torres RJ, Mateos FA, Molano J, Gathoff BS, O'Neill JP, Gundel RM, Trombley L, Puig JG. (2000). Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in thirteen Spanish families. Hum Mutat,15, 383. 20. Jinnah HA, De Gregorio L, Harris JC, Nyhan WL, O'Neill JP. (2000). The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat Res, 463, 309-326. 21. Breese GR, Criswell HE, Duncan GE, Mueller RA. (1990). A dopamine deficiency model of Lesch-Nyhan disease the neonatal-6-OHDA-lesioned rat. Brain Res Bull, 25, 477-484. DOI: 10.1016/0361-9230(90)90240-Z

22. Ernst M, Zametkin AJ, Matochik JA, Pascualvaca D, Jons PH, Hardy C, Hankerson JG, Doudet DJ, Cohen RM. (1996). Presynaptic dopaminergic deficits in Lesch-Nyhan disease. New Engl. J Med, 334, 1568-1572. DOI: 10.1056/NEJM199606133342403 23. "Lesch-Nyhan syndrome". Genetics Home Reference. US National Library of Medicine, Feb. 2013. Web. 24 Jan. 2015. 24. "Lesch-Nyhan Syndrome". NYU Langone Medical Center. Aug. 2014. Web. 25 Jan. 2015. 25. "Gout". Mayo Clinic. 25 Nov. 2014. Web. 24 Jan. 2015. 26. Garca PJ, Torres JR, Mateos F, Ramos T, Arcas J, Buo A, O'Neill P. (2001). The spectrum of Hypoxanthine-Guanine Phosphoribosyltransferase (HPRT) deficiency. Clinical experience based on 22 patients from 18 Spanish families. Medicine (Balt), 80, 102-112. 27. "Dystonias Fact Sheet". National Institute of Neurological Disorders and Stroke. 12 Nov. 2014 Web. 24 Jan. 2015. 28. Schretlen DJ, Harris JC, Park KS, Jinnah HA, del Pozo NO. (2001). Neurocognitive functioning in Lesch-Nyhan disease and partial hypoxanthine-guanine phosphoribosyltransferase deficiency. J Int Neuropsychol Soc, 7, 805-812. 29. Anderson LT, Ernst M. (1994). Self-injury in Lesch-Nyhan disease. J Autism Dev Disord, 24, 67-81. 30. Davidson BL, Tarle SA, Palella TD, Kelley WN. (1989). Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in ten subjects determined by direct sequencing of amplified transcripts. J Clin Invest, 84, 342-346. 31. Olson L, Houlihan D. (2000). A review of behavioral treatments used for Lesch-Nyhan syndrome. Behav Modif, 24, 202-222. 32. Gene Ontology Consortium. An Introduction to the Gene Ontology. Accessed 26 February 2015. 33. Herron, J.C. and Freeman S. (2014). Evolutionary Analysis: Fifth Edition. Glenview, IL: Pearson Education, Inc. 34. Delsuc F, Brinkmann H, Philippe H. (2005). Phylogenomics and the reconstruction of the tree of life. Nat Rev Genet 6:361-375.

35. About BLAST http://www.ncbi.nlm.nih.gov/books/NBK1734/ 36. Gingras AC, Gstaiger M, Raught B, and Aebersold R. (2007). Analysis of protein complexes using mass spectrometry. Nat Rev Mol Cell Biol, 19(4), 645-654.

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