The Lyon laboratory takes an integrated approach to understanding the pathophysiology of severe neuropsychiatric disorders. This includes using technologies such as whole genome sequencing, induced pluripotent stem cells and deep brain stimulation to investigate and/or perturb these conditions. We focus on the discovery of families with rare diseases and/or increased prevalence for syndromes such as intellectual disability, autism, Tourette syndrome and schizophrenia. Once we identify mutations that likely contribute to a disease, we undertake detailed functional studies of these mutations and the biological processes affected. Proving the biological relevance for newly discovered mutations is the major problem, so having access to research participants and derived tissues is critically important, hence the need to engage directly with families.
We are currently elaborating in detail the mechanistic basis of a new rare disease that we described in 2011. This is the first human disease involving a defect in the N-terminal acetylation of proteins, a common (yet vastly understudied) modification of eukaryotic proteins carried out by N-terminal acetyltransferases (NATs). We are calling this disease Ogden Syndrome, in honor of where the first family resides in Ogden, Utah. We are using several different cellular model systems, including yeast and mammalian cells, to better understand the disease pathophysiology and the basic processes of N-terminal acetylation.
The Lyon lab has a long-term research interest in the scientific problem of how genetic background and environmental perturbation influence phenotypic differences, particularly in severe mental illness. This has led us to efforts involving neuromodulation, namely investigating the effects of deep brain stimulation for treatment-refractory obsessive compulsive disorder (OCD). We recently published the first account of this effort, which was the first study in the clinical neurosciences that integrated detailed neuropsychiatric phenotyping, deep brain stimulation (DBS) for OCD, and clinical-grade WGS with management of genetic results in the medical treatment of one person with severe mental illness.