John Jay Gargus

Professor, Physiology & Biophysics
School of Medicine

Professor, Pediatrics
School of Medicine

Director of Center for Autism Research and Translation (UCI CART)
School of Medicine

PH.D., Yale University


M.D., Yale University

Phone: (949) 824-7702
Fax: (949) 824-1762
Email: jjgargus@uci.edu

University of California, Irvine
2056 Hewitt Hall
843 Health Sciences Rd
Mail Code: 3940
Irvine, CA 92697

picture of John Jay  Gargus

Research
Interests
Director UCI CART drug discovery platform for autism; Functional genomics approach to ion channel candidate genes in common complex polygenic disease, and the molecular pathophysiology of inborn errors in signaling, placing a heavy reliance upon function
   
URLs Physiology & Biophysics Home Page
   
Center for Autism Research and Treatment (UCI CART)
   
Scientific American article on Migraine Aug 2008
   
SYMPOSIUM: Co-organizer Society of General Physiologists 2008 annual meeting
   
PUBLIC LECTURE: Autism Spectrum Disorders presentation for Newkirk Center 2010
   
REVIEW: Mitochondrial Component of Calcium Signaling Abnormality in Autism
   
REVIEW: Genetic Calcium Signaling Abnormalities in the Central Nervous System: Seizures, Migraine, and Autism
   
Pediatrics Home Page
   
Channelopathy Foundation
   
Academic
Distinctions
• The 2010 Allen Lecture, The Newkirk Center for Science and Society, Beckman Center of the National Academies of Sciences.
• Organizer & session chair “The Channelopathies” at 11th International Congress of Inborn Errors of Metabolism, 2009
• Co-organizer Society of General Physiologists annual meeting "Calcium Disease" , 2008
• Councilor, American Physiological Society, section of Cell and Molecular Physiology, 2006-2010
• 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 diseases, Organizer and co-chair.
• Councilor, American Physiological Society, section of Cell and Molecular Physiology
• American Physiological Society, Long-Range Planning Committee Member
•Past Plenary Session invited speaker, American Society of Genetics meeting
• Current or Past member of NIH, ACS, AHA and UC Discovery study sections
   
Appointments 1981 - 1983 Postdoctoral Research, Yale University School of Medicine, Departments of Human Genetics and Physiology, Laboratories of E.A. Adelberg and C.W. Slayman.
1983 - 1992 Assistant/Associate Professor of Physiology and Pediatrics, Emory University Department of Physiology, Department of Pediatrics, Section of Medical Genetics.
1989 - 1991 Co-Director, Program in Genetics and Molecular Biology, Emory University.
1992- 2003 Associate Professor IV-V of Physiology & Biophysics, and Pediatrics, Division of Human Genetics, University of California, Irvine.
1996- 2003 Director, Inborn Errors of Metabolism Clinic and Newborn Screening Program, University of California, Irvine.
2003- pres Professor II-V of Physiology & Biophysics and Pediatrics, Division of Human Genetics, University of California, Irvine.
   
Research
Abstract
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. The other field is broadly the molecular pathophysiology of inborn errors in signal transduction via receptors, transporters and channels, a field also covered in a recent invited review. The approach to both areas places a heavy reliance upon functional biophysical studies and molecular pathophysiology in addition to more traditional human molecular genetics.

The first project 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 group subsequently showed 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.

The second project resolves a mitochondrial energy-deficiency endophenotype in a subgroup of patients with autism, initially dealing with a rare subgroup having a recognized 15q chromosomal abnormality, but later studies on typical clinic populations 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.

The third project deals with 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.

Clinical studies 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.
   
Available Technologies
Publications Gargus J.J. (2010) Mitochondrial component of calcium signaling abnormality in autism. In: Autism: oxidative stress, inflammation and immune abnormalities. A. Chauhan, ed. Taylor & Francis. pp 207- 224.
   
  Gargus J.J. (2009) Genetic calcium signaling abnormalities in the CNS: seizures, migraine and autism. The Year in Human & Medical Genetics. Annals of the New York Academy of Sciences. 1151: 133 – 156.
   
  Bezprozvanny I., Gargus, J.J. (2008). 62nd Society of General Physiologists symposium “Calcium: unlocking the mysteries”. Co-organizer and -chair
J. Gen. Physiology 132 (1): 1a-40a.
   
  D.W. Dodick, J. J. Gargus (2008) Why Migraines Strike. Scientific American 299: 56 – 63.
(weblink to Sci Am site:
http://www.sciam.com/article.cfm?id=why-migraines-strike)
   
  Gargus J.J. (2008) Receptor, Transporter and Ion Channel Diseases. In: Neurobiology . R.A. Meyers, eds. Wiley-VCH Verlag GmbH, Weinheim, Volume 2: 669-742.
   
  Gargus, J.J., F. Imtiaz (2008) Mitochondrial energy-deficient endophenotype in autism. Am J Biochem and Biotech 4: 198 - 207.
   
  Bannwarth S, Procaccio V, Rouzier C, Fragaki K, Poole J, Chabrol B, Desnuelle C,
Pouget J, Azulay JP, Attarian S, Pellissier JF, Gargus JJ, Abdenur J, Mozaffar T, Calvas P, Labauge P, Pages M, Wallace DC, Lambert JC, Paquis-Flucklinger V (2007). Rapid identification of mitochondrial DNA (mtDNA) mutations
in neuromuscular disorders by using Surveyor strategy. Mitochondrion 8:136 -45.
   
  Gargus, J.J., C.H. Shih (2007) Monogenic Migraine Syndromes Highlight Novel Drug Targets. Drug Development Research 68:432 - 440.
   
  Gargus, J.J., A. Tournay (2007) Novel mutation confirms seizure locus SCN1A is also FHM3 migraine locus. Ped Neurol 37: 407 - 410.
   
  Ma, S., J. J. Gargus (2007) The Genetics of Neuronal Channelopathies. In: Encyclopedia of Life Sciences. John Wiley & Sons, Ltd: Chichester http://www.els.net/ [DOI: 10.1002/9780470015902.a0020225]
   
  Liang, B., M. Moussaif, C.J. Kuan, J.J. Gargus, Sze, J.Y. (2006) Serotonin targets the DAF-16/FOXO signaling pathway to modulate stress responses. Cell Metabolism 4: 429 – 440. (featured with review by Tissenbaum 415 - 417).
   
  Gargus, J. J. (2006) Ion channel functional candidate genes in polygenic neuropsychiatric disease. Biological Psychiatry, in press.


Blostein, R., L Segal, JJ Gargus. (2006) ATP1A2: un facteur essentiel dans la migraine hémiplégique familiale. Medecine/Sciences 22: in press.


Blostein, R., L Segall, R Scanzano, A Mezzetti, E Purisima, JJ Gargus. (2005) Functional alterations in the alpha2 isoform of the Na,K-ATPase associated with Familial Hemiplegic Migraine Type 2. J. Gen. Physiol 126: 5a-6a.
   
  Gargus JJ (2005) Receptor, Transporter and Ion Channel Diseases. In: Encyclopedia of Molecular Cell Biology and Molecular Medicine . R.A. Meyers, eds. Wiley-VCH Verlag GmbH, Weinheim, Volume 11: 637-711.

Segall L, A Mezzetti, R Scanzano, JJ Gargus, E Purisima, R Blostein. (2005) Alterations in the alpha2 isoform of the Na,K-ATPase associated with Familial Hemiplegic Migraine Type 2. Proc. Nat. Acad. Sci. USA 102:11106-11111.

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.
   
  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: in press.
   
  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.
   
  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.
   
  Rajpoot D., J. J. Gargus (2004) Emergent dialysis for acute hyperammonemia in neonates: Rationale for an aggressive treatment. Pediatr Nephrol: 19(4):390-5.
   
  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.
   
  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: in press.
   
  Sun, G., J.J. Gargus, D.T. Ta, L.E. Vickery (2003) Identification of a novel candidate gene in the iron-sulfer pathway implicated in ataxia-susceptibility: human gene encoding Hsc20 (HscB), a J-type co-chaperone. J Hum Genet: in press
   
  Gargus, J.J. (2003) Unraveling monogenic channelopathies and their implications for complex polygenic disease. Am J Hum Genet 72: 785-803.
   
  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.
   
  Tomita, H., V.G. Shakkittai, G.A. Gutman, G. Sun, W.E. Bunney, M.D. Cahalan, K.G. Chandy, J.J. Gargus (2003) Naturally occurring dominant-negative SK3 channel isoform. Molecular Psychiatry 8: 460 and 766.
   
  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.
   
  Nyhan, W.L., J. J. Gargus, K. Boyle, R. Selby, R. Koch (2002) Progressive neurologic disability in methylmalonic acidemia despite transplantation of the liver. Eur J Pediatr 161: 377-379
   
  Shakkottai, V.G., I. Regaya, H. Wolfe, Z. Fajloun, H. Tomita, M. Fathallah, M. Cahalan, J.J. Gargus, J-M Sabatier, K.G. Chandy (2001). Design and characterization of a highly selective peptide inhibitor of the small conductance calcium-activated K+ channel, SKCa2. J Biol Chem 276:43145-43151
   
  Wang, Y., S. Korman, J. Ye, J.J. Gargus, F. Taroni, B. Garavaglia, N. Longo. (2001). Phenotype and genotype variation in primary carnitine deficiency. Genetics in Medicine 3:387–392.
   
  Miller, M.J., H. Rauer, H. Tomita, H. Rauer, J.J. Gargus, G.A. Gutman, M.D. Cahalan, K.G. Chandy. (2001). Nuclear localization and dominant-negative suppression by a mutant SKCa3 N-terminal channel fragment identified in a patient with schizophrenia. J Biol Chem 276: 27753-27756.
   
  Sun, G., H. Tomita, V.G. Shakkottai, J.J. Gargus. (2001). Genomic organization and promoter analysis of human KCNN3 gene. J. Hum Genet 46: 463-470.
   
  Antonarakis, S.E., J-L Blouin, V.K. Lasseter, C. Gehrig, U. Radhakrishna, G. Nestadt, D.E. Housman, H.H. Kazazian, K. Kalman, G.A. Gutman, E. Fantino, K.G. Chandy, J.J. Gargus, A.E.Pulver. (1999). Lack of linkage or association between schizophrenia and the polymorphic trinucleotide repeat within the KCNN3 gene on chromosome 1q21. Am J Med Genet 88:348-51

   
  Dror, V., Shamir, E., Ghanshani, S., Kimhi, R., Swartz, M., Barak, Y., Weizman, R., Avivi, L., Litmanovitch, T., Fantino, E., Kalman, K., Jones, E.G., Chandy, K.G., Gargus, J.J., Gutman, G.A., Navon, R. (1999). HKCa3/KCNN3 potassium channel gene: association of longer CAG repeats with schizophrenia in Israeli Ashkenazi Jews, expression in human tissues and localization to chromosome 1q21. Molecular Psychiatry 4: 254-260.
   
  Gargus, J.J., Fantino, E., Gutman, G.A. (1998) A piece in the puzzle: an ion channel candidate gene for schizophrenia. Molecular Medicine Today 4:518-524.
   
  Vargus, G.A., Isas, J.M., Fantino, E., Gargus, J.J., Hairgler, H.T. (1998). CCG1/TAFII 250 regulates epidermal growth factor receptor gene transcription in cell cycle mutant ts13. J. Cell. Physiol. 176: 642-7
   
  Chandy, K.G., Fantino, E., Wittekindt,, O., Kalman, K., Tong, L., Ho, T., Gutman, G.A., Crocq, M.-A., Ganguli, R., Nimgaonkar, V., Morris-Rosendahl, D.J., Gargus, J. J. (1998). Isolation of a novel potassium channel gene, hKCa3 containing a polymorphic CAG repeat: candidate for schizophrenia and bipolar disorder? Molecular Psychiatry 3: 32-37.
   
  Ghanshani,S., Coleman, M., Gustavsson, P., Wu, A.L.C., Gargus, J.J., Gutman, G.A.. Dahl, N., Mohrenweiser, H., Chandy, K.G. (1998) Human calcium-activated potassium channel gene KCNN4 maps to chromosome 19q13.2 in the region deleted in diamond-blackfan anemia. Genomics 51:160-161.
   
  Nguyen, H.B., Estacion, M., Gargus, J.J. (1997) Mutations causing achondroplasia and thanatophoric dysplasia alter bFGF-induced calcium signals in human diploid fibroblasts. Human Mol Genet 6: 681-88.
   
  Vargas, G.A., Fantino, E., George-Nascimento, C., Gargus, J.J., Haigler, H.T. (1996). Reduced epidermal growth factor receptor expression in hypohidrotic ectodermal dysplasia. J. Clin. Invest. 97:2426-2432.
   
  Sands, J.M., J.J. Gargus, O. Frohlich, R.B. Gunn and J.P. Kokko (1992). Importance of carrier-mediated urea transport to urine concentrating ability in patients with Jk(a-b-) blood type. J. ASN 2:1689-1696.
   
  Jung, F., Selvaraj , S.,Gargus, J.J. (1992) Blockers of PDGF-activated nonselective cation channel inhibits cell proliferation. Am. J. Physiol.: Cell 262:C1464-C1470.
   
  ISSUED PATENTS

Gargus, J.J. and Estacion, M.
Novel biophysical technique to detect congenital disease.
Patent number 6,183,975. Issued 2/6/2001.

Chandy, K.G., Fantino, E, Gutman, G.A., Kalman, K. and Gargus, J.J. HKCa3/KCNN3 small conductance calcium activated potassium channel: a diagnostic marker and therapeutic target.
Patent numbers 6,165,719. Issued 12/26/2000 and 6,653,100 B1. Issued 11/25/2003.

Tomita, H., Shakkottai, V, Chandy, K.G., Gargus, J.J.
Novel exons of the hSKCa3/KCNN3 gene.
Patent number 7,022,480. Issued 4/4/06.
   
Grants NAAR "Energy-deficient metabolic phenotype in subgroups of autism"
   
NIH R21MH071433-01 “Autism 5HT candidate gene discovery with C. elegans”
   
Doris Duke Clinical Interfaces Award 2005 “A Mitochondrial Basis for Metabolic Syndrome”
   
NIH R01-NS070298 “Mitochondrial etiology of Autism”
   
Autism Speaks “Mitochondrial etiology of Autism”
   
Professional
Societies
American Society of Human Genetics
Society of General Physiologists
Biophysical Society
American Physiological Society
   
Other Experience American Board of Medical Genetics certified
1984

Graduate Programs Developmental Biology and Genetics

Neurobiology

   
Research Centers Center for Autism Research and Treatment
   
Center for Mitochondrial and Molecular Medicine and Genetics (MAMMAG)
   
   
Link to this profile http://www.faculty.uci.edu/profile.cfm?faculty_id=2313
   
Last updated 07/15/2015