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Joseph Gleeson, MD

Joseph Gleeson, MD

Professor, Neurogenetics Laboratory - Dept. Neurosciences and Pediatrics
Secondary Appointments: Senior Staff, Rady Children Hospital; Investigator, Howard Hughes Medical Institute

Contact Information

Leichtag Building, Room 482
University of California, San Diego
9500 Gilman Drive
La Jolla, CA 92093-0665
Office Tel: 858-822-2856
Lab Tel: 858-822-3538
Fax: 858-246-0436
Lab Website:

Research Title
Molecular basis of human neurological disorders

Research Description
The major area of emphasis in my laboratory is the study of the genetic and cell biological basis of human brain development. We start our studies with analysis of disorders of human development, including epileptic disorders, mental retardation, and abnormalities in brain structure. We work to identify one or more genes that is mutated in each of these conditions. The identification of such genes provides tremendous insight, because it informs us about the role of the gene in the human brain. Once a gene for a particular condition has been identified, we work with cell biological and genetic tools to identify the role of the gene in basic neurobiological processes.

We have been focusing on two major conditions that are important cause of disease in humans. The first is disordered neuronal migration. Neurons that populate the cerebral cortex are not born within the gray matter, but instead they are born along the lining of the lateral ventricle. These young neurons then migrate great distances to achieve proper positioning within the correct lamina of the developing cortex. When this is disrupted, cortical gyri and sulci are malformed and the cortex is improperly laminated. We work on the doublecortin family of genes, encoding novel microtubule-associated proteins, to understand their role in brain development. When mutated, doublecortin gives rise to human lissencephaly, consisting of a smooth brain. We are currently focused on understanding the role of this gene family in migration, in establishing cell polarity, and in organization of the microtubule cytoskeleton.

The other condition of focus in the lab is congenital ataxia, where humans are born with severe balance disturbances and malformations of the cerebellum. We work on the most common of these disorders known as Joubert syndrome where the midline of the cerebellum (known as the vermis) is completely absent. We have identified the first genes for this condition, which encode novel proteins. There is evidence to suggest that in this condition the major axonal tracts fail to form properly, suggesting that the genes also play important roles in axonal guidance. We are currently studying the molecular basis of Joubert syndrome, identifying additional Jouberin genes, and working to understand the role of these genes in brain development.

Akizu N, Cantagrel V, Schroth J, Cai N, Vaux K, McCloskey D, Naviaux RK, Van Vleet J, Fenstermaker AG, Silhavy JL, Scheliga JS, Toyama K, Morisaki H, Sonmez FM, Celep F, Oraby A, Zaki MS, Al-Baradie R, Faqeih EA, Saleh MA, Spencer E, Rosti RO, Scott E, Nickerson E, Gabriel S, Morisaki T, Holmes EW, Gleeson JG. AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder. Cell. 2013 Aug 1;154(3):505-17.

Novarino G, El-Fishawy P, Kayserili H, Meguid NA, Scott EM, Schroth J, Silhavy JL, Kara M, Khalil RO, Ben-Omran T, Ercan-Sencicek AG, Hashish AF, Sanders SJ, Gupta AR, Hashem HS, Matern D, Gabriel S, Sweetman L, Rahimi Y, Harris RA, State MW, Gleeson JG. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science. 2012 Oct 19;338(6105):394-7.

Lee JH, Huynh M, Silhavy JL, Kim S, Dixon-Salazar T, Heiberg A, Scott E, Bafna V, Hill KJ, Collazo A, Funari V, Russ C, Gabriel SB, Mathern GW,Gleeson JG. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet. 2012 Jun 24;44(8):941-5.

Dixon-Salazar TJ, Silhavy JL, Udpa N, Schroth J, Bielas S, Schaffer AE, Olvera J, Bafna V, Zaki MS, Abdel-Salam GH, Mansour LA, Selim L, Abdel-Hadi S, Marzouki N, Ben-Omran T, Al-Saana NA, Sonmez FM, Celep F, Azam M, Hill KJ, Collazo A, Fenstermaker AG, Novarino G, Akizu N, Garimella KV, Sougnez C, Russ C, Gabriel SB, Gleeson JG. Exome sequencing can improve diagnosis and alter patient management. Sci Transl Med. 2012 Jun 13;4(138):138ra78.

Lee JH, Silhavy JL, Lee JE, Al-Gazali L, Thomas S, Davis EE, Bielas SL, Hill KJ, Iannicelli M, Brancati F, Gabriel SB, Russ C, Logan CV, Sharif SM, Bennett CP, Abe M, Hildebrandt F, Diplas BH, Attié-Bitach T, Katsanis N, Rajab A, Koul R, Sztriha L, Waters ER, Ferro-Novick S, Woods CG, Johnson CA, Valente EM, Zaki MS, Gleeson JG. Evolutionarily assembled cis-regulatory module at a human ciliopathy locus. Science. 2012 Feb 24;335(6071):966-9.

Lee JE, Silhavy JL, Zaki MS, Schroth J, Bielas SL, Marsh SE, Olvera J, Brancati F, Iannicelli M, Ikegami K, Schlossman AM, Merriman B, Attié-Bitach T, Logan CV, Glass IA, Cluckey A, Louie CM, Lee JH, Raynes HR, Rapin I, Castroviejo IP, Setou M, Barbot C, Boltshauser E, Nelson SF, Hildebrandt F, Johnson CA, Doherty DA, Valente EM, Gleeson JG. CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium. Nat Genet. 2012 Jan 15;44(2):193-9

Cantagrel V, Lefeber DJ, Ng BG, Guan Z, Silhavy JL, Bielas SL, Lehle L, Hombauer H, Adamowicz M, Swiezewska E, De Brouwer AP, Blümel P, Sykut-Cegielska J, Houliston S, Swistun D, Ali BR, Dobyns WB, Babovic-Vuksanovic D, van Bokhoven H, Wevers RA, Raetz CR, Freeze HH, Morava E, Al-Gazali L, Gleeson JG. SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell. 2010 Jul 23;142(2):203-17.