The McNally Laboratory studies genetic diseases that affect heart and muscle. These genetic mutations produce heart and muscle dysfunction through a number of different biological pathways. It is our goal to better understand how, when and why these diseases develop and progress. In some cases, individuals with genetic mutations may be protected from developing disease and we are interested in using genetics to define the pathways that protect these individuals.
We use approaches that include whole genome analysis, induced pluripotent stem cell generation, mouse and Drosophila models and gene editing. The lab includes graduate students, postdoctoral fellows and highly skilled technicians. We also host undergraduate and postbaccalaurate trainees who are interested in developing new approaches.
Defining and understanding rare genetic variation
In the clinical setting, genetic testing for inherited cardiomyopathy and skeletal muscle disease now uses gene panels, where 50-100 genes are assessed simultaneously. With the improvements in sequencing technology, notably massively parallel next generation sequencing, it is now more feasible to use broad-based sequencing to identify novel genes and alleles responsible for human disease. In order to facilitate the analysis of whole genome sequencing, we harness the power of high performance and supercomputing to improve the speed and accuracy of genome analysis.
Identifying modifiers of genetic disease
The rationale to search for genetic modifiers is stimulated by the observation that the same individual mutation often results in a range of phenotype from mild to severe. Discovering genetic modifiers is useful because it uncovers pathways useful for therapeutic targeting and also because these modifiers can better predict prognosis. We conducted unbiased genomewide mapping for modifiers using mice with muscle and heart disease. Using an intercross strategy, we conducted genomewide scans and have now identified two different modifiers, Ltbp4 and Anxa6, that change outcome. The first of these, Ltbp4, encodes the latent TGFb binding protein 4 and has now been shown to modify human disease.
Membrane repair proteins
Mutations in dysferlin, a distinct membrane-associated protein in muscle, also lead to inherited muscle disease. Loss of dysferlin is associated with delayed repair and resealing after disruption of the plasma membrane. We characterized myoferlin, a protein highly related to dysferlin. Both myoferlin and dysferlin are multi C2 domain containing proteins, and in other proteins, like the synaptotagmins, C2 domains bind phospholipids. We were the first to demonstrate that C2 domains of dysferlin and myoferlin bind phospholipids in a Ca2+ sensitive manner. Our work has also implicated ferlin proteins as interacting with EHD proteins and playing a broad role in membrane trafficking in muscle extending to the genesis of the transverse tubule network.
Mutations in nuclear membrane proteins, especially the genes encoding lamin A/C, emerin, and nesprin, also lead to genetically mediated heart and muscle. These mutations also affect the heart where they target the cardiac conduction system. The mechanism by which mutations in the genes encoding these broadly expressed proteins lead to tissue specific phenotypes is not fully understood and we are investigating the function of these proteins.
Many mutations that cause heart failure disrupt cardiac metabolism. We are testing mouse models and human cells to learn the relationship between cardiac metabolism and progression to heart failure.
- Supercomputing for the parallel analysis of whole human genome sequencing
- Whole genome sequencing to reliably identify rare mutations
- Latent TGFb binding protein is a modifier of heart and muscle disease
- Annexin A6 modifies muscle repair from injury
- Developing new tools to interpret rare genetic variants
- Use mouse genetics to identify modifiers of genetic disease
- Generation of cell models for human disease with induced pluripotent stem cells (iPSCs)
- Improving gene editing methods in human iPSCs and testing novel genetic corrective therapies