Purdue University Graduate School
Swetha Ramadesikan_Dissertation_Final_062320.pdf (4.02 MB)

Role of Ocrl1-dependent signaling abnormalities and mutation heterogeneity in Lowe Syndrome cellular phenotypes

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posted on 2020-06-23, 20:00 authored by Swetha RamadesikanSwetha Ramadesikan

Lowe Syndrome (LS) is a lethal developmental disease characterized by mental retardation, cataracts at birth and kidney dysfunction. LS children unfortunately die by adolescence from renal failure. The gene responsible for the disease (OCRL1) encodes an inositol 5’ phosphatase Ocrl1. In addition to its 5’ phosphatase domain, this protein has other domains that allow protein-protein interactions, facilitating diverse sub-cellular distribution and functions. LS patient cells lacking Ocrl1 display defects in cell spreading, ciliogenesis and vesicle trafficking. Currently the mechanisms underlying these cellular defects are not known, and hence no LS-specific therapies exist.

We have uncovered the mechanisms underlying two LS-specific cellular phenotypes- namely cell spreading and ciliogenesis and identified 2 FDA-approved candidates- statins and rapamycin that could revert these abnormalities. We found that Ocrl1-deficient cells exhibit hyperactivation in mTOR signaling, resulting in ciliogenesis as well as autophagy defects, which were rescued by administering rapamycin. We also identified a novel RhoGTPase signaling-dependent cell adhesion defect in LS patient cells which resulted in focal adhesion abnormalities and sensitivity to fluid shear stress (critical for kidney function). Both RhoGTPase signaling dependent cell spreading and adhesion defects were corrected by treatment with statins.

Importantly, over 200 unique mutations in OCRL1 cause LS and patients demonstrate heterogeneity in symptoms. However, the correlation between genotype and cellular phenotypes is unknown. We have determined that different OCRL1 patient mutations have a differential impact on the two cellular phenotypes described above. Mutants exhibit behavior, sub-cellular distribution and cellular phenotypes unique to the domain and relevant to LS pathogenesis. We also propose that a subset of non-catalytic phosphatase domain mutations are conformationally affecting the protein, suggesting that LS has a conformational disease component. Importantly, we tested an FDA-approved drug, 4-phenyl butyric acid (4-PBA), used as a therapeutic in conformational diseases and found that it could revert phenotypes and restore the catalytic activity of these mutants. These findings collectively contribute to provide the cellular basis for LS patient heterogeneity as well as to propose a conformational disease component for LS (allowing the use of chemical chaperones as a therapeutic strategy for a subset of LS patients). Together, we hope that these studies will help lay the foundation of better prognosis and tailoring personalized therapeutic strategies for LS patients.


Purdue Research Foundation Fellowship

Ross Fellowship- Purdue Graduate School


Degree Type

  • Doctor of Philosophy


  • Biological Sciences

Campus location

  • West Lafayette

Advisor/Supervisor/Committee Chair

Dr. Ruben C Aguilar

Additional Committee Member 2

Dr. Donna Fekete

Additional Committee Member 3

Dr. Philip Low

Additional Committee Member 4

Dr. Donald Ready

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