Dr. Richard Steet

Active Research Projects

Defining the molecular and cellular pathogenesis of rare genetic disorders. The Steet laboratory continues to focus on the pathogenesis of several different rare diseases, including the lysosomal storage disorder mucolipidosis II or I-cell disease, and the congenital disorders of glycosylation (CDG). Supported by both public and private grants, his lab’s current focus on lysosomal disorders (done in collaboration with Dr. Heather Flanagan-Steet) is to understand how glycosaminoglycans and lysosomal exocytosis modulate extracellular cathepsin K activity to drive abnormal cartilage development. His group is currently developing new zebrafish models to expand this work beyond mucolipidosis II. Dr. Steet’s team is broadly interested in defining the pathogenic mechanisms that underlie these disorders in the hope of using this information to identify new therapies.

Functional characterization of genetic variation. This area of research has undergone a major expansion in Dr. Steet’s laboratory over the last four years and will remain a significant focus in the future. His laboratory utilizes various cell systems and patient-derived cell lines to study how different variants impact the function of the encoded proteins and cellular pathways. A major area of focus is the functional characterization of IDUA variants that are identified as part of newborn screening efforts for MPSI. This research has been led by GGC staff scientist, Dr. Seok-Ho Yu, and is done in collaboration with Dr. Laura Pollard (Lead Director of the Biochemical Laboratory) and Dr. Flanagan-Steet (Director of Functional Studies). This team has developed a cell-based platform that can be used to determine the relative specific activity of each variant iduronidase enzyme – a value that can be used to stratify the different variants and determine whether they might be disease-causing.

There are numerous ongoing functional studies projects in Dr. Steet’s laboratory that highlight the collaborative nature of this research. These projects include: 1) Functional characterization of novel LMNB1 variants associated with microcephaly and other neurological phenotypes; 2) Defining the effects of novel UQCRC1 variants on mitochondrial function (external collaborator: Norma Frizzell, UofSC); 3) Unraveling the functional consequences of de novo DDX23 variants (external collaborators: Lela Lackey and Jennifer Mason, Clemson); and 4) Resolving the impact of variants in ALDH18A1 and the involvement of specific biochemical pathways on disease pathogenesis (external collaborators: Max Colonna and Art Edison, University of Georgia).

Select Publications:

  • Colonna MB, Moss T, Mokashi S, Srikanth S, Jones JR, Foley JR, Skinner C, Lichty A, Kocur A, Wood T, Stewart TM, Casero RA, Flanagan-Steet H, Edison AS, Lyons MJ, Steet R. Functional Assessment of Homozygous ALDH18A1 Variants Reveals Alterations in Amino Acid and Antioxidant Metabolism. Hum Mol Genet. 2022 Sep 6:ddac226. doi: 10.1093/hmg/ddac226. PMID: 36067040.
  • 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 Jul;23(7):1305-1314. PMID: 33731878; PMCID: PMC8263489.
  • 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):88. PMID: 33198351; 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. PMID: 32910914; PMCID: PMC7536573.

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Lucy's Story

Lucy's Story

When our daughter Lucy had a metabolic crisis at 7 days old, we were shocked and devastated to find out that she was born with a rare genetic disorder (MSUD). Her newborn screening results did not make it back in time to prevent the crisis, and no one at our local hospital was familiar with the disease. They did not know how to treat her. Calls were made to Greenwood Genetic Center to confirm her diagnosis and guide her care. Dr. Champaigne and Ami...

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