Director of Research, Greenwood Genetic Center
Email: rsteet@ggc.org
Phone: 864-388-1807
Biosketch
A native of upstate New York, Dr. Steet received his B.A. in biochemistry from Colgate University in 1994 and his Ph.D. from the University of Colorado-Boulder in 2000. Following postdoctoral studies in the laboratory of Dr. Stuart Kornfeld at Washington University School of Medicine in St. Louis, he began his independent research career at the Complex Carbohydrate Research Center on the University of Georgia campus in 2006. During this time, Dr. Steet expanded his research interests into the chemical glycobiology arena, helping to develop methods for the profiling of the cell surface glycoproteins. He was promoted to the rank of Associate Professor with tenure in 2012 and Full Professor in 2018. Dr. Steet moved his laboratory to the Greenwood Genetic Center in 2018 where he currently serves as the Director of Research and the Head of the JC Self Research Institute. He holds adjunct professor positions at both Clemson University (in the Department of Genetics and Biochemistry) and the University of South Carolina School of Medicine (in the Department of Anatomy and Cell Biology). He actively investigates pathogenic mechanisms and treatments for numerous genetic disorders in collaboration with his wife and colleague, Dr. Heather Flanagan-Steet. Dr. Steet is a dedicated advocate for rare disease, serving on the Scientific Advisory Boards for ISMRD and the MPS society, and is involved with numerous research networks focused on rare metabolic conditions.
Research
The research interests of Dr. Steet’s laboratory lie at the intersection of glycobiology, lysosomal biology and human disease. Our current focus is aimed at defining the pathogenic mechanisms that underlie the lysosomal storage disorders and congenital disorders of glycosylation (CDG) using both zebrafish and cultured cells. In these systems, we employ a powerful combination of genetic, biochemical and microscopic methods to uncover the pathogenic cascades of these disorders and explore new ways to treat them. We are currently leveraging our experience defining disease mechanisms to functionally characterize novel disease/gene associations and variants of uncertain significance.
Recent Publications
Yu SH, Wang T, Wiggins K, Louie RJ, Merino EF, Skinner C, Cassera MB, Meagher K, Goldberg P, Rismanchi N, Chen D, Lyons MJ, Flanagan-Steet H, Steet R. Lysosomal cholesterol accumulation contributes to the movement phenotypes associated with NUS1 haploinsufficiency. Genet Med. 2021 Mar 17;. doi: 10.1038/s41436-021-01137-6. [Epub ahead of print] PubMed PMID: 33731878; NIHMSID:NIHMS1689971.
Phoomak C, Cui W, Hayman TJ, Yu SH, Zhao P, Wells L, Steet R, Contessa JN. The translocon-associated protein (TRAP) complex regulates quality control of N-linked glycosylation during ER stress. Sci Adv. 2021 Jan;7(3). doi: 10.1126/sciadv.abc6364. Print 2021 Jan. PubMed PMID: 33523898; PubMed Central PMCID: PMC7810369.
Yu SH, Pollard L, Wood T, Flanagan-Steet H, Steet R. A Biochemical Platform to Define the Relative Specific Activity of IDUA Variants Identified by Newborn Screening. Int J Neonatal Screen. 2020 Nov 12;6(4). doi: 10.3390/ijns6040088. PubMed PMID: 33198351; PubMed Central PMCID: PMC7711455.
Lu PN, Moreland T, Christian CJ, Lund TC, Steet RA, Flanagan-Steet H. Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation. JCI Insight. 2020 Oct 15;5(20). doi: 10.1172/jci.insight.133019. PubMed PMID: 33055423; PubMed Central PMCID: PMC7605527.
Cristofoli F, Moss T, Moore HW, Devriendt K, Flanagan-Steet H, May M, Jones J, Roelens F, Fons C, Fernandez A, Martorell L, Selicorni A, Maitz S, Vitiello G, Van der Hoeven G, Skinner SA, Bollen M, Vermeesch JR, Steet R, Van Esch H. De Novo Variants in LMNB1 Cause Pronounced Syndromic Microcephaly and Disruption of Nuclear Envelope Integrity. Am J Hum Genet. 2020 Oct 1;107(4):753-762. doi: 10.1016/j.ajhg.2020.08.015. Epub 2020 Sep 9. PubMed PMID: 32910914; PubMed Central PMCID: PMC7536573.
Naumchik BM, Gupta A, Flanagan-Steet H, Steet RA, Cathey SS, Orchard PJ, Lund TC. The Role of Hematopoietic Cell Transplant in the Glycoprotein Diseases. Cells. 2020 Jun 5;9(6). doi: 10.3390/cells9061411. Review. PubMed PMID: 32517081; PubMed Central PMCID: PMC7348849.
Ates KM, Wang T, Moreland T, Veeranan-Karmegam R, Ma M, Jeter C, Anand P, Wenzel W, Kim HG, Wolfe LA, Stephen J, Adams DR, Markello T, Tifft CJ, Settlage R, Gahl WA, Gonsalvez GB, Malicdan MC, Flanagan-Steet H, Pan YA. Deficiency in the endocytic adaptor proteins PHETA1/2 impairs renal and craniofacial development. Dis Model Mech. 2020 May 26;13(5). doi: 10.1242/dmm.041913. PubMed PMID: 32152089; PubMed Central PMCID: PMC7272357.
Barnes JW, Aarnio-Peterson M, Norris J, Haskins M, Flanagan-Steet H, Steet R. Upregulation of Sortilin, a Lysosomal Sorting Receptor, Corresponds with Reduced Bioavailability of Latent TGFβ in Mucolipidosis II Cells. Biomolecules. 2020 Apr 26;10(5). doi: 10.3390/biom10050670. PubMed PMID: 32357547; PubMed Central PMCID: PMC7277838.
Neighbors A, Moss T, Holloway L, Yu SH, Annese F, Skinner S, Saneto R, Steet R. Functional analysis of a novel mutation in the TIMM8A gene that causes deafness-dystonia-optic neuronopathy syndrome. Mol Genet Genomic Med. 2020 Mar;8(3):e1121. doi: 10.1002/mgg3.1121. Epub 2020 Jan 5. PubMed PMID: 31903733; PubMed Central PMCID: PMC7057109.
Han SO, Haynes AC, Li S, Abraham DM, Kishnani PS, Steet R, Koeberl DD. Evaluation of antihypertensive drugs in combination with enzyme replacement therapy in mice with Pompe disease. Mol Genet Metab. 2020 Feb;129(2):73-79. doi: 10.1016/j.ymgme.2019.10.005. Epub 2019 Oct 17. PubMed PMID: 31645300; PubMed Central PMCID: PMC7002209.
Klaver E, Zhao P, May M, Flanagan-Steet H, Freeze HH, Gilmore R, Wells L, Contessa J, Steet R. Selective inhibition of N-linked glycosylation impairs receptor tyrosine kinase processing. Dis Model Mech. 2019 Jun 5;12(6). doi: 10.1242/dmm.039602. PubMed PMID: 31101650; PubMed Central PMCID: PMC6602306.
Yu SH, Zhao P, Prabhakar PK, Sun T, Beedle A, Boons GJ, Moremen KW, Wells L, Steet R. Defective mucin-type glycosylation on α-dystroglycan in COG-deficient cells increases its susceptibility to bacterial proteases. J Biol Chem. 2018 Sep 14;293(37):14534-14544. doi: 10.1074/jbc.RA118.003014. Epub 2018 Jul 26. PubMed PMID: 30049793; PubMed Central PMCID: PMC6139567.
Kondo Y, Fu J, Wang H, Hoover C, McDaniel JM, Steet R, Patra D, Song J, Pollard L, Cathey S, Yago T, Wiley G, Macwana S, Guthridge J, McGee S, Li S, Griffin C, Furukawa K, James JA, Ruan C, McEver RP, Wierenga KJ, Gaffney PM, Xia L. Site-1 protease deficiency causes human skeletal dysplasia due to defective inter-organelle protein trafficking. JCI Insight. 2018 Jul 26;3(14). doi: 10.1172/jci.insight.121596. eCollection 2018 Jul 26. PubMed PMID: 30046013; PubMed Central PMCID: PMC6124414.
Flanagan-Steet H, Christian C, Lu PN, Aarnio-Peterson M, Sanman L, Archer-Hartmann S, Azadi P, Bogyo M, Steet RA. TGF-ß Regulates Cathepsin Activation during Normal and Pathogenic Development. Cell Rep. 2018 Mar 13;22(11):2964-2977. doi: 10.1016/j.celrep.2018.02.066. PubMed PMID: 29539424; PubMed Central PMCID: PMC6247414.
Aarnio-Peterson M, Zhao P, Yu SH, Christian C, Flanagan-Steet H, Wells L, Steet R. Altered Met receptor phosphorylation and LRP1-mediated uptake in cells lacking carbohydrate-dependent lysosomal targeting. J Biol Chem. 2017 Sep 8;292(36):15094-15104. doi: 10.1074/jbc.M117.790139. Epub 2017 Jul 19. PubMed PMID: 28724630; PubMed Central PMCID: PMC5592684.
Berger RP, Dookwah M, Steet R, Dalton S. Glycosylation and stem cells: Regulatory roles and application of iPSCs in the study of glycosylation-related disorders. Bioessays. 2016 Dec;38(12):1255-1265. doi: 10.1002/bies.201600138. Epub 2016 Sep 26. Review. PubMed PMID: 27667795; PubMed Central PMCID: PMC5214967.
Sun T, Yu SH, Zhao P, Meng L, Moremen KW, Wells L, Steet R, Boons GJ. One-Step Selective Exoenzymatic Labeling (SEEL) Strategy for the Biotinylation and Identification of Glycoproteins of Living Cells. J Am Chem Soc. 2016 Sep 14;138(36):11575-11582. doi: 10.1021/jacs.6b04049. Epub 2016 Sep 1. PubMed PMID: 27541995; PubMed Central PMCID: PMC5067740.
Flanagan-Steet H, Matheny C, Petrey A, Parker J, Steet R. Enzyme-specific differences in mannose phosphorylation between GlcNAc-1-phosphotransferase αβ and γ subunit deficient zebrafish support cathepsin proteases as early mediators of mucolipidosis pathology. Biochim Biophys Acta. 2016 Sep;1860(9):1845-53. doi: 10.1016/j.bbagen.2016.05.029. Epub 2016 May 27. PubMed PMID: 27241848; PubMed Central PMCID: PMC4949139.
Flanagan-Steet H, Aarnio M, Kwan B, Guihard P, Petrey A, Haskins M, Blanchard F, Steet R. Cathepsin-Mediated Alterations in TGFß-Related Signaling Underlie Disrupted Cartilage and Bone Maturation Associated With Impaired Lysosomal Targeting. J Bone Miner Res. 2016 Mar;31(3):535-48. doi: 10.1002/jbmr.2722. Epub 2015 Oct 13. PubMed PMID: 26404503; PubMed Central PMCID: PMC4808492.
Yu SH, Zhao P, Sun T, Gao Z, Moremen KW, Boons GJ, Wells L, Steet R. Selective Exo-Enzymatic Labeling Detects Increased Cell Surface Sialoglycoprotein Expression upon Megakaryocytic Differentiation. J Biol Chem. 2016 Feb 19;291(8):3982-9. doi: 10.1074/jbc.M115.700369. Epub 2016 Jan 5. PubMed PMID: 26733198; PubMed Central PMCID: PMC4759176.
Gurda BL, De Guilhem De Lataillade A, Bell P, Zhu Y, Yu H, Wang P, Bagel J, Vite CH, Sikora T, Hinderer C, Calcedo R, Yox AD, Steet RA, Ruane T, O’Donnell P, Gao G, Wilson JM, Casal M, Ponder KP, Haskins ME. Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII. Mol Ther. 2016 Feb;24(2):206-216. doi: 10.1038/mt.2015.189. Epub 2015 Oct 8. PubMed PMID: 26447927; PubMed Central PMCID: PMC4817811.
Han SO, Pope R, Li S, Kishnani PS, Steet R, Koeberl DD. A beta-blocker, propranolol, decreases the efficacy from enzyme replacement therapy in Pompe disease. Mol Genet Metab. 2016 Feb;117(2):114-9. doi: 10.1016/j.ymgme.2015.09.012. Epub 2015 Oct 3. PubMed PMID: 26454691; PubMed Central PMCID: PMC4755835.
Sutton DA, Yu SH, Steet R, Popik VV. Cyclopropenone-caged Sondheimer diyne (dibenzo[a,e]cyclooctadiyne): a photoactivatable linchpin for efficient SPAAC crosslinking. Chem Commun (Camb). 2016 Jan 11;52(3):553-6. doi: 10.1039/c5cc08106h. Epub 2015 Nov 5. PubMed PMID: 26538499; PubMed Central PMCID: PMC4689622.