Investigator, Howard Hughes Medical Institute
Senior Attending Physician
Laboratory of Pediatric Brain Disease
Dr. Gleeson seeks to understand the causes for pediatric brain diseases and, when possible, find treatments for otherwise untreatable conditions. To identify the genes responsible for recessive disorders, Dr. Gleeson recruits patients in regions where marriage within extended families is relatively common, simplifying the search for inherited mutations. Ultimately, these results contribute to the understanding of human brain development.
Understanding the causes of brain disorders, particularly among children, presents unique challenges. The brain is less accessible than other organs; typical screening tests, such as MRI, are not as predictive as once thought; and it has become apparent that multiple mutations may, individually, cause the same disorder, while any given mutation may lead to many different clinical presentations.
Genetic sequencing technology allows researchers to look across all possible genes for a culprit, without introducing any bias or preconceptions. Dr. Gleeson uses high throughput exome and genome sequencing to investigate the causes of pediatric brain disorders among children in highly susceptible families. In addition to aiding diagnosis and treatment, these discoveries support Dr. Gleeson’s overarching goal: to better understand the development of the human brain.
In earlier work, Dr. Gleeson identified the genetic origins of the neurological disorders Joubert syndrome and double cortex syndrome. The Gleeson lab is now investigating the mechanism by which Joubert syndrome can arise through nearly 30 different genetic causes. As the tools for gene sequencing have improved, the lab has expanded its focus to encompass a spectrum of devastating childhood neurological disorders, including autism, epilepsy, intellectual disability, and structural brain disorders.
Because individual mutations can be very rare, Dr. Gleeson collaborates with physician-scientists in the Middle East, North Africa, and Central Asia, where consanguineous marriage between relatives as close as first cousins is common, to recruit affected families. Using samples from these families, the Gleeson laboratory identifies likely variations and builds a model, using a variety of methods, to predict the mechanism responsible.
To date, the Gleeson laboratory has enrolled more than 4,000 families and examined more than 4,000 exomes, among the largest single-lab experience in the U.S. From the growing candidate gene list, the lab prioritizes genes that suggest possible treatments, often for conditions thought to be untreatable. In recent work, the Gleason lab identified a rare form of autism and traced its cause to a mutation in the gene BCKDK that blocks the action of an enzyme that prevents the metabolism of essential branched-chain amino acids. Recent work points to the effectiveness of treatment with these amino acids for this form of autism and epilepsy.
Currently, most diagnostic sequencing is limited to the exome, the small portion of the genome containing DNA that codes for protein. However, Dr. Gleeson and others intend to use the uniquely accessible genetics of consanguineous families to help make sense of the rest of the genome, its so-called dark matter, and to transition to whole-genome sequencing, in collaboration with the New York Genome Center.
B.A. in chemistry and economics, 1986
University of California, San Diego
University of Chicago Pritzker School of Medicine
Internship in pediatrics, 1991–1992
Residency in pediatrics, 1992–1993
Residency and fellowship in neurology, 1993–1996
Boston Children’s Hospital
Harvard Medical School, 1995–1999
Assistant Professor, 1999–2004
Associate Professor, 2004–2008
University of California, San Diego
Senior Staff, 2002–2014
Rady Children’s Hospital, San Diego
Adjunct Professor, 2016–
The Rockefeller University
Senior Attending Physician, 2014–
The Rockefeller University Hospital
Howard Hughes Medical Institute
Searle Scholar, 2000
Klingenstein Fellowship, 2001
Ray Thomas Edwards Award, 2002
Burroughs Wellcome Fund Award, 2005
Theodore Bullock Award, 2006
Simons Autism Foundation Research Initiative Investigator, 2010
National Academy of Medicine
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Schaffer, A.E. et al. CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration. Cell 157, 651–663 (2014).
Novarino, G. et al. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343, 506–511 (2014).
Akizu, N. et al. AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder. Cell 154, 505–517 (2013).
Novarino, G. et al. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science 338, 394–397 (2012).