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Investigating targettable pathways in Robinow Syndrome

Szabo Rogers, Heather (2020) Investigating targettable pathways in Robinow Syndrome. In: Pitt Momentum Fund 2020, University of Pittsburgh, Pittsburgh, Pa. (Unpublished)

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Individuals with Robinow syndrome, a genetic condition, are born with a wider midface, and shorter stature. In addition to the congenital anomalies, a subset of adolescent patients with Robinow syndrome develop bony overgrowths that impinge on the cranial nerve foramina leading to significant co-morbidities including pain. Robinow Syndrome is caused by mutations in core components of the Wnt/Planar cell polarity (Wnt/PCP) signaling pathway. Wnt/PCP signaling regulates neighbor relationships through the protein-protein interactions of its core components including Prickle1 and Dishevelled. We have determined that the Prickle1Bj/Bj mice are an excellent model for Robinow Syndrome. The Prickle1Bj/Bj mice have a wider midface, and shortened limbs. While, thus far, there is no report of Robinow patients with Prickle1 mutations, Prickle1 protein function serves as the common mechanistic link between all of the known patient mutations in Robinow Syndrome. Prickle1Bj/Bj growth plates have randomized chondrocyte polarity as a result of decreased protein-protein interactions between Prickle1Bj and Dvl2 or Dvl3. The consequence of the diminished protein interactions is increased Hedgehog signaling in the Prickle1Bj/Bj cranial base compared to controls. In response to increased HH signaling, the Prickle1Bj/Bj cranial base growth plates undergo precocious maturation which prevents its proximal-distal expansion resulting in the wider midface, and shorter stature. In addition, the Prickle1Bj/Bj primary cilia are shortened and swollen. In this proposal, I will test the hypothesis that Prickle1 is necessary for ciliogenesis, and the swollen cilia in Prickle1Bj/Bj mutants results in increased HH signaling. We will determine if the increased HH signaling is the primary cause of the Prickle1Bj/Bj skeletal anomalies by dampening HH signaling. In addition, we will determine if dampening HH signaling in human patient derived fibroblasts can modify the disease phenotype.


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Item Type: Conference or Workshop Item (Poster)
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Szabo Rogers, Heatherhsrogers@pitt.eduhsrogers0000-0002-7921-8031
Centers: Other Centers, Institutes, Offices, or Units > Office of Sponsored Research > Pitt Momentum Fund
Date: 2020
Event Title: Pitt Momentum Fund 2020
Event Type: Other
DOI or Unique Handle: 10.18117/kkft-mf32
Schools and Programs: School of Dental Medicine > Dental Science
Refereed: No
Other ID: 3472
Date Deposited: 24 Feb 2020 16:26
Last Modified: 17 Feb 2023 18:44


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