Mitchell D Shub

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Journals/Publications

• Bayer, M., Goldenring, J. R., Goldsmith, J. D., Hagen, S. J., Jimenez, L., Kaji, I., Kalashyan, M., Kolobova, E., Oller, H., Raghunathan, K., Roland, J. T., Shub, M. D., & Thiagarajah, J. R. (2023). Therapy Development for Microvillus Inclusion Disease using Patient-derived Enteroids. bioRxiv (Cold Spring Harbor Laboratory). doi:10.1101/2023.01.28.526036
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  ABSTRACT Microvillus Inclusion Disease (MVID), caused by loss-of-function mutations in the motor protein Myosin Vb (MYO5B), is a severe infantile disease characterized by diarrhea, malabsorption, and acid-base instability, requiring intensive parenteral support for nutritional and fluid management. Human patient-derived enteroids represent a model for investigation of monogenic epithelial disorders but are a rare resource from MVID patients. We developed human enteroids with different loss-of function MYO5B variants and showed that they recapitulated the structural changes found in native MVID enterocytes. Multiplex Immunofluorescence imaging of patient duodenal tissues revealed patient-specific changes in localization of brush border transporters. Functional analysis of electrolyte transport revealed profound loss of Na + /H + exchange (NHE) activity in MVID patient enteroids with near-normal chloride secretion. The chloride channel-blocking anti-diarrheal drug, Crofelemer, dose-dependently inhibited agonist-mediated fluid secretion. MVID enteroids exhibited altered differentiation and maturation versus healthy enteroids. Inhibition of Notch signaling with the γ-secretase inhibitor, DAPT, recovered apical brush border structure and functional Na + /H + exchange activity in MVID enteroids. Transcriptomic analysis revealed potential pathways involved in the rescue of MVID cells including serum- and glucocorticoid-induced protein kinase 2 (SGK2), and NHE regulatory factor 3 (NHERF3). These results demonstrate the utility of patient-derived enteroids for developing therapeutic approaches to MVID. Conflict-of-interest statement The authors have declared that no conflict of interest exists.
• Pohl, J., Shub, M., Trevelline, E., Ingebo, K., Silber, G., Rayborn, N., Holve, S., & Hu, D. (1999). A cluster of microvillous inclusion disease in the Navajo population. Journal of Pediatrics, 134(1). doi:10.1016/S0022-3476(99)70380-X
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  We report 4 unrelated patients with characteristic microscopic findings of microvillous inclusion disease (MID) with early-onset phenotype. All 4 patients came from the Navajo reservation in northern Arizona. A literature search revealed a fifth unrelated Navajo child with MID. The unusually high incidence in this population indicates that a founder effect might be responsible for an increased frequency of this rare genetic disorder in the Navajo. It is recommended that all Navajo infants presenting with severe diarrhea during early infancy undergo investigation for MID.