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FACULTY

Adolescent Medicine
Allergy & Immunology
Cardiology
Critical Care/PICU
Endocrinology
General Pediatrics
Hematology/Oncology
Human Genetics & Metabolism
James Bartley, M.D., Ph.D.
Maureen Bocian, M.D.
Jose Camacho, M.D.
Kenneth W. Dumars, M.D.
Pamela Flodman, M.S., CGC
John Jay Gargus, M.D., Ph.D.
Taosheng Huang, M.D., Ph.D.
Virginia Kimonis, M.D.
Vincent Procaccio, M.D., Ph.D.
Roxanne Ruzicka, M.S., CGC
Moyra Smith, M.D., Ph.D.
M. Anne Spence, Ph.D.
Kathy Steinhaus French,MS,CGC
Ann Walker, M.A., CGC
Douglas C. Wallace, Ph.D.
Michael Zaragoza, M.D., Ph.D.

Infectious Disease
Neonatal/Perinatal Medicine
Nephrology
Neurology
Pulmonology
Child Development Center
General Clinical Research Center

• Position:
• Professor of Pediatrics
• - Human Genetics Division & Metabolism
• Professor of Physiology & Biophysics


• Please also visit Dr. Gargus at:
• www.ucihs.uci.edu/pandb/
  www.igb.uci.edu/people/faculty.html#


• EDUCATION


• Graduate Education:
• PhD, Yale University


• Medical School Education:
• MD, Yale University


• Internship & Residency:
• Yale Pediatrics


• HONORS & AWARDS


• National Headache Foundation Annual Lectureship Award, 2006
• Doris Duke Foundation Clinical Interfaces Award 2005, Key Investigator
• Federation of American Societies for Experimental Biology (FASEB) Visiting Professor Award, 2005
• American Heart Association Young Investigators Forum, Co-organizer and Co-chair
• 2003 Southern California Biotechnology Symposium, Gene discovery in complex polygenic disease, Organizer and co-chair
• Current NIH, DDF, and NAAR grant recipient
• Past Plenary Session invited speaker, American Society of Genetics meeting
• Current or Past member of NIH, ACS, AHA, and UC Discovery study sections
• Patents issued on four inventions of genetic technology


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• MEMBERSHIPS AND AFFILIATIONS


• Professional Societies:
• American Society of Human Genetics
• Society of General Physiologists
• Biophysical Society
• American Physiological Society


• RESEARCH


• Interests:
• Functional genomics
• Diseases of ion pumps and channels
• Complex polygenic neuropsychiatric disease
• Molecular pathophysiology of inborn errors in signal transduction


• Summary:
• There are two major research thrusts on-going in the Gargus lab. The first is broadly a functional genomics approach to ion pumps and channels as candidate genes in common complex polygenic disease, a field he recently covered in invited reviews (Gargus, 2006 "Ion channel functional candidate genes in multigenic neuropsychiatric disease". Biological Psychiatry, in press; Gargus, 2003 "Unraveling monogenic channelopathies and their implications for complex polygenic disease" Am J Hum Genet 72: 785-803). The other field is broadly the molecular pathophysiology of inborn errors in signal transduction via receptors, transporters and channels, a field also covered in an invited review (Gargus, 2005 "Receptor, Transporter and Ion Channel Diseases" In: Encyclopedia of Molecular Cell Biology and Molecular Medicine. R.A. Meyers, eds. Wiley-VCH Verlag BmbH, Weinheim). The approach to both areas places a heavy reliance upon functional biophysical studies and molecular pathophysiology in addition to more traditional human molecular genetics.


• SELECTED RECENT PUBLICATIONS


• 1. Kaunisto MA, Harno H, Vanmolkot KR, Gargus JJ, Sun G, Hamalainen E, Liukkonen E, Kallela M, Van Den Maagdenberg AM, Frants RR, Farkkila M, Palotie A, Wessman M. (2004). A novel missense ATP1A2 mutation in a Finnish family with familial hemiplegic migraine type 2. Neurogenetics 5:141-6.


• 2. Segall L, R Scanzano, MA Kaunisto, M Wessman, A Palotie, JJ Gargus, R Blostein (2004) Kinetic alterations due to a missense mutation in the Na,K-ATPase ?2 subunit cause familial hemiplegic migraine type 2. J Biol Chem 279:43692-43696.


• 3. Segall L, A Mezzetti, R Scanzano, JJ Gargus, E Purisima, R Blostein. (2005) Alterations in the ?2 isoform of the Na,K-ATPase associated with Familial Hemiplegic Migraine Type 2. Proc. Nat. Acad. Sci. USA 102:11106-11111.


• 4. Blostein, R., L Segall, R Scanzano, A Mezzetti, E Purisima, JJ Gargus. (2005) Functional alterations in the ?2 isoform of the Na,K-ATPase associated with Familial Hemiplegic Migraine Type 2. Invited presentation. International Na/K ATPase meeting. J. Gen. Physiology, in press.


• 5. Blostein, R., L Segall, JJ Gargus. (2005) ATP1A2: un facteur essentiel dans la migraine hémiplégique familiale. Medecine/Sciences 22: in press.


• The first two of these five recent papers took advantage of a large Finnish family with Familial Hemiplegic Migraine (FHM) to define a new migraine gene (ATP1A2) and resolve its mechanism of pathophysiology. The mutant disease-causing allele was recognized to alter a conserved amino acid in a subunit of the major energy consuming enzyme of the body, the Na/K ATPase, the ion pump that establishes the cation gradients across all cell membranes which are tapped by ion channels for electrical activity. The final four papers show that this mutation, and three other mutations found in the disease, altered the kinetics of partial reactions of the pump and its overall flux, the very first such mutations recognized to create a disease by altering the kinetics of this ion pump. The functional alterations were shown to disturb the crystallographic structure of the pump and could be recognized to be a likely participant in production of the aura, a prodromal state that is the hallmark of the disease. The hope is to identify how these lesions predispose to the disease at the cellular level, and thereby develop novel molecular targets against which to screen for novel therapeutics for migraine.


• 6. Filipek, P.A., J. Juranek, M. Smith, E.R. Ramos, L.Z.Mays, M. Bocian, D. Masser-Frye, T. M. Laulhere, C. Modahl, M.A. Spence, J.J. Gargus (2003) Evidence of mitochondrial dysfunction in autistic patients with 15q inverted duplication. Ann Neurol 53: 801- 804.


• 7. Filipek, P.A., J. Juranek, C. Cummings, K.A. Gallardo, P. Yuan, J. J. Gargus (2004) Relative carnitine deficiency in autism. J Autism Devel Disorders 34: 615 -623.


• These two recent papers resolve a mitochondrial energy-deficiency endophenotype in a subgroup of patients with autism, the first dealing with a rare subgroup having a recognized 15q chromosomal abnormality, but the later based on a typical clinic population having no recognizable chromosomal abnormalities. Subjects are now being enrolled to extend these studies through a new National Alliance for Autism Research (NAAR) grant to further resolve this endophenotype using expression profiling with DNA microarray technology, and, through a new National Institutes of Mental Health (NIMH) grant, we hope to use this clinical endophenotype to guide discovery in the C. elegans model genetic organism of those genes that should be candidate genes involved in autism since they link the inexplicable cluster of metabolic phenotypes seen. The hope is that genetic dissection of this phylogenetically highly conserved system will lead to new candidate gene targets in autism that can be tested in patients and that will be helpful in the design of new diagnostics and, ultimately, therapeutics for this disease.


• 8. Tomita, H., V.G. Shakkittai, G.A. Gutman, G. Sun, W.E. Bunney, M.D. Cahalan, K.G. Chandy, J.J. Gargus (2003) Novel truncated isoform of SK3 potassium channel is a potent dominant-negative regulator of SK currents: implications in schizophrenia. Molecular Psychiatry 8: 524 – 535.


• 9. Wittekindt O.H., V. Visan, H. Tomita, F. Imtiaz, J. J. Gargus, F. Lehmann-Horn, S. Grissmer, D. J. Morris Rosendahl (2004) A scyllatoxin-insensitive isoform of the human SK3 channel: Molecular Pharmacol 65: 788-801.


• 10. Kolski-Andreaco A., H. Tomita, V.G. Shakkottai, G. Gutman, M. Cahalan, J.J. Gargus, K.G. Chandy (2004) SK3-1C: a dominant-negative suppressor of SKCa and IKCa channels. J Biol Chem 279: 6893-904.


• These three recent papers reveal novel isoforms of an ion channel candidate gene our group has previously implicated in schizophrenia. In them we uncover a potent pathogenic mechanism in which a negative-dominant inhibitory mutation achieves a supra-dominant inhibition of an entire family of ion channels that play a critical pacemaker role in the brain. Current work is focused on this mechanism of pathogenesis and the cellular origin of the organismal phenotype in fly, worm and mouse transgenetic models.


• 11. Gargus, J. J., K. Boyle, M Bocian, D.S. Roe, C. Vianey-Saban, C.R. Roe (2003). Respiratory complex II defect in sibs associated with a symptomatic secondary block in fatty acid oxidation. J Inherit Metab Dis: 26: 659 – 670.


• 12. Sun, G., J.J. Gargus, D.T. Ta, L.E. Vickery (2003) Identification of a novel candidate gene in the iron-sulfur pathway implicated in ataxia-susceptibility: human gene encoding Hsc20 (HscB), a J-type co-chaperone. J Hum Genet: 48: 415- 419.


• 13. Rajpoot D., J. J. Gargus (2004) Emergent dialysis for acute hyperammonemia in neonates: Rationale for an aggressive treatment. Pediatr Nephrol: 19(4):390-5.


• These three recent papers reveal a spectrum of developments in the resolution of genetic neurological disease: first, a new metabolic genetic disease and phenotype, reflecting an important interaction of fatty acid oxidation with the mitochondrial respiratory chain; second, a new candidate gene for ataxia-susceptibility, pointing at the importance of iron-sulfur centers in ataxia pathogenesis; and third, a neuropathic mechanism that alters therapeutic approaches to metabolic genetic syndromes in newborns.


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