The Manton Center for Orphan Disease Research
Chiara Manzini, PhD
Gene identification in rare genetic disorders disrupting cell-extracellular matrix interactions
The goal of this proposal is to study the genetics of rare disorders affecting the interactions between cells and the extracellular matrix (ECM), the meshwork of proteins and sugars surrounding cells and tissues. The ECM is an important regulator of cellular differentiation and organogenesis, and defects in its structure often affect a multitude of systems in the body. Brain, eyes and muscle in particular rely heavily on the ECM for differentiation and are frequently concurrently affected with different levels of severity. Because these disorders are extremely genetically and clinically heterogeneous, determining guidelines for genetic testing and identifying the multiple undiscovered disease genes has been very challenging.
We will use state-of-the-art sequencing technologies to sequence every gene in the genome of each affected individual to bypass this heterogeneity and explore each family/subject individually. We will then use the zebrafish as an animal model to explore the functional effects of the genetic variants we identified to determine whether such changes replicate the phenotypes observed in the patients. This work will likely yield multiple new candidate genes responsible for disorders of cell-ECM interaction, help determine the relative contribution to each gene to ease the establishment of guidelines for genetic testing and provide new insight into the mechanisms responsible for brain, eye
and muscle development.