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.
Gholson Lyon started his independent career in 2009 at the University of Utah, where he led the group that first used exon capture and sequencing to identify the genetic basis of an entirely new, idiopathic disorder, which was named Ogden Syndrome, in honor of where the first family resides in Ogden, Utah. This discovery received wide press coverage in 2011, including in Nature, where Eric Topol predicted that this was just the beginning of a tidal wave of many more idiopathic disorders being investigated by exome and whole genome sequencing. This prediction has certainly come to pass, as many hundreds of researchers worldwide are identifying genetic mutations in many disorders. Ogden Syndrome was also 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). Ogden syndrome is X-linked, and the affected males have a Ser37Pro change in hNaa10, the catalytic subunit of NatA, the major human NAT involved in the co-translational acetylation of proteins. Structural modeling of the human NatA and its S37P mutant highlight differences in regions involved in catalysis and at the interface between hNaa10 and the auxiliary subunit hNaa15. Biochemical data further demonstrate a reduced catalytic capacity and an impaired interaction between hNaa10 S37P and hNaa15 as well as hNaa50 (NatE), another interactor of the NatA complex. N-terminal acetylome analyses revealed a decreased acetylation of only ~30 NatA and NatE substrates in Ogden syndrome cells, supporting the genetic findings and our hypothesis regarding reduced Nt-acetylation of a small subset of NatA/NatE-type substrates as an etiology for Ogden Syndrome. The Lyon lab is now using several different model systems, including yeast, transgenic mice, and mammalian cell culture, 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.