Director of Functional Studies, Greenwood Genetic Center
Dr. Flanagan-Steet’s scientific training started with a B.A. in Biology from Carleton College (Northfield, MN). In 2001 she received her PhD in Molecular, Cellular, and Developmental Biology from the University of Colorado, Boulder. From there she pursued post-doctoral studies in neurobiology with Dr. Joshua Sanes at Washington University in St. Louis. During her post-doctoral training Dr. Flanagan-Steet pioneered the use of zebrafish to model rare genetic disorders. This effort seeded a long-term collaboration with her husband, Dr. Richard Steet. She began her independent career at the University of Georgia, where she established multiple models and methods to uncover pathogenic mechanisms of both lysosomal storage disorders and congenital disorders of glycosylation. In 2018 after 12 productive years at the University of Georgia, Dr. Flanagan-Steet and her zebrafish relocated to the Greenwood Genetic Center (GGC). At the GGC Dr. Flanagan-Steet serves Director of Functional Studies. In this role she works closely with the Center’s tremendous team to advance our understanding of genetic disorders. In parallel she continues to pursue pathogenic mechanisms driving disease.
Dr. Flanagan-Steet’s research has largely focused on defining the mechanisms governing early tissue development. This has ranged from investigating how neuromuscular synapses form to development of the embryonic heart and craniofacial skeleton. For nearly two decades Dr. Flanagan-Steet’s efforts have centered on defining the molecular and cellular mechanisms underlying pathogenesis of rare genetic diseases, including several lysosomal storage disorders and the congenital disorders of glycosylation. Her work on genetic diseases has primarily involved generating zebrafish models to investigate gene function and disease pathogenesis. Her work pioneered the use of zebrafish to model rare inherited diseases, bringing new insight into the molecular initiators and mechanisms underlying pathogenesis of the lysosomal storage disorder mucolipidosis II. The success of these studies has been augmented by her long time collaboration with her colleague and spouse, Dr. Richard Steet.
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.
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.
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.
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.
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.
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.
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.