Trainee Author: Julie Craft Van De Weghe, PhD
Senior Postdoc Research Fellow
Department of Pediatrics, University of Washington
(Photo courtesy Van De Weghe)
Van De Weghe JC, Rusterholz TDS, Latour B, et al. Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish. AJHG. 2017 Jun 15;101(1):23-36.
This study uses both clinical and zebrafish studies to identify a new gene implicated in ciliopathies, a group of disorders that is distinguished by their overlapping clinical features and unifying cilium dysfunction. Specifically, it focused on Joubert syndrome, a recessive neurodevelopmental disorder that is defined by what looks like a “molar tooth” during MRI studies of affected patients.
The study identified ARMC9 through exome and targeted sequencing of a patient cohort of over 500 individuals. Using immortalized retinal epithelial cells, the authors found that ARMC9 localized to the ciliary basal body, similar to other Joubert syndrome-associated proteins. Using a zebrafish model, the authors engineered frameshift mutations and found that armc9-mutated zebrafish displayed ciliopathy phenotypes, such as a reduction of cilia in brain ventricles, and a curved body axis.
The understanding of ciliopathies and Joubert syndrome have had significant advances, but multiple gene candidates have been found and common cellular mechanisms of dysfunction are not yet clear. This work adds to our understanding of underlying causes of Joubert syndrome and other ciliopathies.
ASHG: Could you describe your research for us?
Dr. Van De Weghe: I am keenly interested in both normal ciliary biology and the molecular pathophysiology of ciliopathies. Cilia are cylindrical, microtubule-based organelles that project from most cells and acts as a cellular antenna, sensing mechanical, chemical, and light input, as well as mediating multiple signaling pathways.
When dysfunctional, ciliopathy disorders arise and exhibit overlapping clinical multi-organ features, including developmental delay, variable intellectual disability, limb patterning defects, retinal dystrophy leading to blindness, liver fibrosis, and cystic kidney disease leading to kidney failure.
ASHG: What are your career goals?
Dr. Van De Weghe: I look forward to a career as a leader of my own research group, satiating my deep curiosity about the role of cilia in human development and disease. I strive to make meaningful contributions to our collective knowledge of cilia biology and the consequences to human health upon disruption of ciliary homeostasis. I am intellectually invested and engaged to spend my career translating my lab discoveries into treatments for people affected by these disorders.
ASHG: Why did you choose genetics as your field of study?
Dr. Van De Weghe: I harness the awesome, synergistic power of genetics and cell biology to investigate the molecular pathophysiology of Joubert syndrome (JS). To do so, it is essential to 1) identify the complete genetic spectrum of JS and 2) form a more complete understanding of how JS-associated proteins function together.
This project started as disease gene discovery, but has developed into a fruitful collaboration combining protein interaction screens, human cell biology, and zebrafish modeling. Stay tuned for the next installment!
ASHG: If you could pick three words that describe yourself, what would they be?
Dr. Van De Weghe: Creative, Idiosyncratic, Tenacious.