Heads of Laboratories
Joseph G. Gleeson, M.D.
Investigator, Howard Hughes Medical Institute
Laboratory of Pediatric Brain Disease
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 based on preconceptions about the disorder. Dr. Gleeson uses high-throughput exome sequencing to investigate the causes of pediatric brain disorders, often among children in highly susceptible families. The results have implications for not only the diagnosis, but also the treatment of patients. And the discoveries also support Dr. Gleeson’s overarching goal: to better understand the development of the human brain.
Dr. Gleeson’s work originally focused on Joubert syndrome and Double cortex syndrome. Joubert syndrome is an inherited malformation of the cerebellum and brain stem. The laboratory established Joubert syndrome as one of the ‘ciliopathies’, disorders due to defects in function of neuronal primary cilia. The Gleeson lab established more than six different genetic causes and is currently investigating the mechanisms by which the disorder arises. He also identified the cause for Double Cortex syndrome, which is due to mutations in the doublecortin gene that cause defects in migration of neurons to the cerebral cortex. As the tools for gene sequencing have improved, he has expanded his focus to encompass a spectrum of devastating childhood neurological disorders, including autism, epilepsy, intellectual disability and structural disorders.
Because disorders caused by single-gene mutations are extremely scarce within the general population, 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. In these families, two unaffected parents often produce more than one affected child. Using samples from these families, the Gleeson laboratory identifies likely variations and builds a model, using stem cells, mice, cell biology or biochemistry-based methods, to predict the mechanism responsible.
To date, the Gleeson laboratory has enrolled more than 3,000 families and examined more than 4,000 exomes, the largest single-lab experience in the US. From the growing candidate gene list, the lab prioritizes candidate genes that suggest possible treatments, often for conditions thought to be untreatable. In recent work, the Gleeson lab identified a rare form of autism that involves epileptic seizures and intellectual deficits in three Middle Eastern families, and pinpointed its cause to be a mutation in the gene BCKDK. This mutation 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 dietary branched chain amino acids to treat 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.
With the dual goals of improving diagnosis and redefining disorders based on their genetic causes, rather than their symptoms, Dr. Gleeson also hopes to form collaborations with neurodevelopmental specialists in New York City in order to obtain sequences of patients’ genomes early on during the diagnostic process.
Dr. Gleeson received his bachelor’s degree in chemistry from the University of California, San Diego in 1986, and earned his medical degree in 1991 from the University of Chicago’s Pritzker School of Medicine with honors. He completed a residency in pediatric neurology at Children’s Hospital in Boston then postdoctoral work at Harvard Medical School. In 1999, he joined the neuroscience faculty at the University of California, San Diego and established the Center for Brain Development. He moved to Rockefeller in 2014. Dr. Gleeson has been a Howard Hughes Medical Institute investigator since 2008.
Dr. Gleeson has received the Searle Scholars Award in 2000, the Klingenstein Award in Neurosciences in 2001, The Ray Thomas Edwards Award in Neurosciences in 2002, the Burroughs Wellcome Fund Award in Translational Research in 2005 and the Theodore Bullock Award in Neuroscience in 2006. He was named an investigator of the Simons Autism Foundation Research Initiative in 2010 and was elected to the Association of American Physicians, and Institute of Medicine in 2013.
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Novarino, G. et al. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343, 506–11 (2014).
Akizu, N. et al. AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder. Cell 154, 505–17 (2013).
Novarino, G. et al. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy.
Science 338, 394–7 (2012).
Lee, J.H. et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet. 44, 941–5 (2012).
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