Vanderbilt University School of Medicine

Summar, Marshall L. , M.D.
Adjoint Professor of Molecular Physiology and Biophysics

Lab Url: N/A

Phone Number: 343-4755


Summar, Marshall's picture

Office Address   Mailing Address

1175 MRB IV

1175J MRB IV Center for Human Genetic Research / Program in Translational Genetics 37232-0007

Research Keywords
urea cycle, mutation, carbamyl phosphate synthetase, nitric oxide, glutathione, mapping, polymorphism, Enzyme action, Gene regulation, Gene therapy, Genetics, Genome, Genomics, Human Genetics, Molecular medicine, Mutation, Physiology, Polymorphism, Protein structure,Apoptosis,Biochemistry,Cardiac function,Chromatin,Chromosome,DNA synthesis,Enzyme action,Gene regulation,Gene therapy,Genetics,Genome,Genomics,Heart,Human Genetics,Molecular medicine,Mutation,Polymorphism,Protein Structure,Pulmonary,Recombination,RNA editing,Transcription,Translation

Research Description
The key focus of my laboratory is the exploration of functional polymorphisms in rate-limiting enzymes in biochemical processes and their effects under environmental stress (Enviromentally Determined Genetic Expression, E.D.G.E.) . This work started with carbamyl phosphate synthetase I (CPSI), which controls flow through the hepatic urea cycle. We have found changes in this enzyme which affect the availability of downstream products such as citrulline and arginine. These molecules are the precursors for nitric oxide synthesis. We have found effects of these CPSI polymorphisms and altered urea cycle flow in a number of groups including: bone marrow transplant recipients, neonates developing persistent pulmonary hypertension, post-cardiac surgery patients, and normal patients tested with bradykinin. We are also exploring polymorphisms we have identified in the enzyme complex controlling glutathione production (gamma-glutamyl cysteine synthetase, GCLC and GCLR subunits). With our collaborators, we are looking at effects of these in the groups listed above as well as Alzheimer?s patients, Hepatitis C patients, and sickle cell anemia (with an ethnic specific GCLC poly). With Dr. Nancy Brown we have found a number of polymorphisms in the enzyme processing bradykinin, dipeptidyl pepditase IV (DPPIV). We are studying the effects of this in patients developing angioedema with blood pressure medications. With Dr. Paul Moore we are examining the role of polymorphisms in beta-adrenergic receptors on patients with asthma in relation to their responsiveness to treatment. With Dr. Asha Kallianpur, we have examined the role of changes in iron storage (referred to as hemochromatosis) in bone marrow transplantation and in the causes of breast cancer. With Drs. Arnold Strauss, Kong Chen, and Naji Abumrad, we are examining the nature and role of polymorphisms in fatty acid oxidation and their role in fatty liver injury. These projects interlock in many ways and this has led to a collaborative group at Vanderbilt called the E.D.G.E. group. This work has led to a collaborative intervention project between myself and Dr. Christman to explore the introduction of urea cycle intermediates in bone marrow transplant patients to prevent hepatic veno-occlusive disease as well as a clinical trial of urea cycle intermediates in post-cardiac surgery patients.
My laboratory has continued our original work on the molecular defects and normal structure/function of human CPSI. Our laboratory determined the genomic structure of this enzyme and serves as the only international referral laboratory for determining the molecular defects in patients with CPSI deficiency (CPSID). We have created expression constructs for this enzyme which we have shared with a number of investigators. We are also using these vectors to test the kinetic/stability effects of our CPSI polymorphisms and CPSID missense mutations. Our work with CPSI deficiency is now focusing on the large number of RNA processing defects we have found in our mutation analysis. These include a number of changes resulting in intron retention and RNA degradation. With Dr. Angela Eeds and Wade-Martin?s, we have built a bacterial artificial chromosome system with eukaryotic episomal replication for the study of genetic changes affecting RNA editing, protein structure, and promoter elements. We have used the model to study RNA processing defects leading to nonsense mediated decay.

Clinical Research Description
We have a multi-center collaborative project looking at the long term outcome of patients with rare inborn errors of metabolism involving the urea cycle. We also are investigating the role of ammonia or nitrogen scavenging drugs (phenylacetate and phenylbutyrate) developed for urea cycle disorders in more common clinical diseases involving liver dysfunction which also lead to hyperammonemia.
In collaboration with Dr. Rick Barr, pediatric critical care, we are examining the role of introducing nitric oxide precursor (citrulline) into pediatric cardiac surgery patients to modify the incidence of post-surgical pulmonary hypertension. With the neonatology group we are planning a project to examine the role of nitric oxide precursor (citrulline) in infants with persistent pulmonary hypertension of the newborn.
With our collaborator Dr. Brian Christman, we are conducting an intervention trial with patients undergoing bone marrow transplantation to offset the treatment related complications using biochemical intermediates. With Dr. Heidi Smith, we are looking at measures of oxidant injury in patients undergoing cardiac surgery as they relate to exposure to oxygen and other surgery related factors. With Dr. Nancy Brown we are looking at genetic and biochemical markers of angioedema risk in patients on anti-hypertensive therapy. With Dr. Paul Moore we are looking at genetic risk factors to response to beta agonists.


Clinical Interests
Processes involving nitrogen metabolism. Hepatic encephalopathy. Use of nitrogen scavengers. Oxidant injury in severe clinical situations. Down Syndrome research and aging.

Ciarleglio, CM, Ryckman, KK, Servick, SV, Hida, A, Robbins, S, Wells, N, Hicks, J, Larson, SA, Wiedermann, JP, Carver, K, Hamilton, N, Kidd, KK, Kidd, JR, Smith, JR, Friedlaender, J, McMahon, DG, Williams, SM, Summar, ML, Johnson, CH. Genetic Differences in Human Circadian Clock Genes among Worldwide Populations. J Biol Rhythms, 23(4), 330-40, 2008. PMCID:2579796

Summar, ML, Dobbelaere, D, Brusilow, S, Lee, B. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr, , , 2008. PMCID:2675643

Barr, FE, Tirona, RG, Taylor, MB, Rice, G, Arnold, J, Cunningham, G, Smith, HA, Campbell, A, Canter, JA, Christian, KG, Drinkwater, DC, Scholl, F, Kavanaugh-McHugh, A, Summar, ML. Pharmacokinetics and safety of intravenously administered citrulline in children undergoing congenital heart surgery: potential therapy for postoperative pulmonary hypertension. J Thorac Cardiovasc Surg, 134(2), 319-26, 2007.

Canter, JA, Summar, ML, Smith, HB, Rice, GD, Hall, LD, Ritchie, MD, Motsinger, AA, Christian, KG, Drinkwater, DC, Scholl, FG, Dyer, KL, Kavanaugh-McHugh, AL, Barr, FE. Genetic variation in the mitochondrial enzyme carbamyl-phosphate synthetase I predisposes children to increased pulmonary artery pressure following surgical repair of congenital heart defects: a validated genetic association study. Mitochondrion, 7(3), 204-10, 2007. PMCID:1929167

Eeds, AM, Mortlock, D, Wade-Martins, R, Summar, ML. Assessing the functional characteristics of synonymous and nonsynonymous mutation candidates by use of large DNA constructs. Am J Hum Genet, 80(4), 740-50, 2007. PMCID:1852709

Eeds, AM, Hall, LD, Yadav, M, Willis, A, Summar, S, Putnam, A, Barr, F, Summar, ML. The frequent observation of evidence for nonsense-mediated decay in RNA from patients with carbamyl phosphate synthetase I deficiency. Mol Genet Metab, 89(1-2), 80-6, 2006.

Moore, PE, Cunningham, G, Calder, MM, DeMatteo, AD, Peeples, ME, Summar, ML, Peebles, RS. Respiratory syncytial virus infection reduces beta2-adrenergic responses in human airway smooth muscle. Am J Respir Cell Mol Biol, 35(5), 559-64, 2006. PMCID:2643275

Smith, HA, Canter, JA, Christian, KG, Drinkwater, DC, Scholl, FG, Christman, BW, Rice, GD, Barr, FE, Summar, ML. Nitric oxide precursors and congenital heart surgery: a randomized controlled trial of oral citrulline. J Thorac Cardiovasc Surg, 132(1), 58-65, 2006.

Caldovic, L, Morizono, H, Panglao, MG, Lopez, GY, Shi, D, Summar, ML, Tuchman, M. Late onset N-acetylglutamate synthase deficiency caused by hypomorphic alleles. Hum Mutat, 25(3), 293-8, 2005.

Canter, JA, Eshaghian, A, Fessel, J, Summar, ML, Roberts, LJ, Morrow, JD, Sligh, JE, Haines, JL. Degree of heteroplasmy reflects oxidant damage in a large family with the mitochondrial DNA A8344G mutation. Free Radic Biol Med, 38(5), 678-83, 2005.

Hulgan, T, Haas, DW, Haines, JL, Ritchie, MD, Robbins, GK, Shafer, RW, Clifford, DB, Kallianpur, AR, Summar, M, Canter, JA. Mitochondrial haplogroups and peripheral neuropathy during antiretroviral therapy: an adult AIDS clinical trials group study. AIDS, 19(13), 1341-9, 2005.

Kallianpur, AR, Hall, LD, Yadav, M, Byrne, DW, Speroff, T, Dittus, RS, Haines, JL, Christman, BW, Summar, ML. The hemochromatosis C282Y allele: a risk factor for hepatic veno-occlusive disease after hematopoietic stem cell transplantation. Bone Marrow Transplant, 35(12), 1155-64, 2005.

King, LS, Singh, RH, Rhead, WJ, Smith, W, Lee, B, Summar, ML. Genetic counseling issues in urea cycle disorders. Crit Care Clin, 21(4 Suppl), S37-44, 2005.

Lee, B, Singh, RH, Rhead, WJ, Sniderman King, L, Smith, W, Summar, ML. Considerations in the difficult-to-manage urea cycle disorder patient. Crit Care Clin, 21(4 Suppl), S19-25, 2005.

Moore, JH, Boczko, EM, Summar, ML. Connecting the dots between genes, biochemistry, and disease susceptibility: systems biology modeling in human genetics. Mol Genet Metab, 84(2), 104-11, 2005.

Singh, RH, Rhead, WJ, Smith, W, Lee, B, King, LS, Summar, M. Nutritional management of urea cycle disorders. Crit Care Clin, 21(4 Suppl), S27-35, 2005.

Smith, W, Kishnani, PS, Lee, B, Singh, RH, Rhead, WJ, Sniderman King, L, Smith, M, Summar, M. Urea cycle disorders: clinical presentation outside the newborn period. Crit Care Clin, 21(4 Suppl), S9-17, 2005.

Summar, ML, Barr, F, Dawling, S, Smith, W, Lee, B, Singh, RH, Rhead, WJ, Sniderman King, L, Christman, BW. Unmasked adult-onset urea cycle disorders in the critical care setting. Crit Care Clin, 21(4 Suppl), S1-8, 2005.

Kallianpur, Asha R, Hall, Lynn D, Yadav, Meeta, Christman, Brian W, Dittus, Robert S, Haines, Jonathan L, Parl, Fritz F, Summar, Marshall L. Increased prevalence of the HFE C282Y hemochromatosis allele in women with breast cancer. Cancer Epidemiol Biomarkers Prev, 13(2), 205-12, 2004.

Summar, Marshall L, Gainer, James V, Pretorius, Mias, Malave, Hector, Harris, Stephanie, Hall, Lynn D, Weisberg, Alec, Vaughan, Douglas E, Christman, Brian W, Brown, Nancy J. Relationship between carbamoyl-phosphate synthetase genotype and systemic vascular function. Hypertension, 43(2), 186-91, 2004.

Summar, Marshall L, Hall, Lynn, Christman, Brian, Barr, Frederick, Smith, Heidi, Kallianpur, Asha, Brown, Nancy, Yadav, Meeta, Willis, Alecia, Eeds, Angela, Cermak, Emma, Summar, Samantha, Wilson, Ann, Arvin, Molly, Putnam, Allison, Wills, Melissa, Cunningham, Gary. Environmentally determined genetic expression: clinical correlates with molecular variants of carbamyl phosphate synthetase I. Mol Genet Metab, 81 Suppl, 12-9, 2004.

Williams, SM, Ritchie, MD, Phillips, JA, Dawson, E, Prince, M, Dzhura, E, Willis, A, Semenya, A, Summar, M, White, BC, Addy, JH, Kpodonu, J, Wong, LJ, Felder, RA, Jose, PA, Moore, JH. Multilocus analysis of hypertension: a hierarchical approach. Hum Hered, 57(1), 28-38, 2004.

Barr, Frederick E, Beverley, Heidi, VanHook, Kristin, Cermak, Emma, Christian, Karla, Drinkwater, Davis, Dyer, Karrie, Raggio, Noel T, Moore, Jason H, Christman, Brian, Summar, Marshall. Effect of cardiopulmonary bypass on urea cycle intermediates and nitric oxide levels after congenital heart surgery. J Pediatr, 142, 26-30, 2003.

Summar, M L, Hall, L D, Eeds, A M, Hutcheson, H B, Kuo, A N, Willis, A S, Rubio, V, Arvin, M K, Schofield, J P, Dawson, E P. Characterization of genomic structure and polymorphisms in the human carbamyl phosphate synthetase I gene. Gene, 311, 51-7, 2003.

Willis, Alecia S, Freeman, Michael L, Summar, Samantha R, Barr, Frederick E, Williams, Scott M, Dawson, Elliott, Summar, Marshall L. Ethnic diversity in a critical gene responsible for glutathione synthesis. Free Radic Biol Med, 34, 72-6, 2003.

Sekhar, Konjeti R, Spitz, Douglas R, Harris, Stephanie, Nguyen, Trung T, Meredith, Michael J, Holt, Jeffrey T, Gius, David, Marnett, Lawrence J, Summar, Marshall L, Freeman, Michael L, Guis, David. Redox-sensitive interaction between KIAA0132 and Nrf2 mediates indomethacin-induced expression of gamma-glutamylcysteine synthetase. Free Radic Biol Med, 32, 650-62, 2002.

Spiekerkoetter, Ute, Eeds, Angela, Yue, Zou, Haines, Jonathan, Strauss, Arnold W, Summar, Marshall. Uniparental disomy of chromosome 2 resulting in lethal trifunctional protein deficiency due to homozygous alpha-subunit mutations. Hum Mutat, 20, 447-51, 2002.

Pearson, D L, Dawling, S, Walsh, W F, Haines, J L, Christman, B W, Bazyk, A, Scott, N, Summar, M L. Neonatal pulmonary hypertension--urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl J Med, 344, 1832-8, 2001.

Summar, M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr, 138, S30-9, 2001.

Summar, M, Tuchman, M. Proceedings of a consensus conference for the management of patients with urea cycle disorders. J Pediatr, 138, S6-10, 2001.

Dasouki, MJ, Cogan, J, Summar, ML, Neblitt, W, Foroud, T, Koller, D, Phillips, JA. Heterogeneity in hereditary pancreatitis. Am J Med Genet, 77(1), 47-53, 1998.

Summar, M L. Molecular genetic research into carbamoyl-phosphate synthase I: molecular defects and linkage markers. J Inherit Metab Dis, 21 Suppl 1, 30-9, 1998.

Sekhar, KR, Long, M, Long, J, Xu, ZQ, Summar, ML, Freeman, ML. Alteration of transcriptional and post-transcriptional expression of gamma-glutamylcysteine synthetase by diethyl maleate. Radiat Res, 147(5), 592-7, 1997.

Hunley, T E, Julian, B A, Phillips, J A, Summar, M L, Yoshida, H, Horn, R G, Brown, N J, Fogo, A, Ichikawa, I, Kon, V. Angiotensin converting enzyme gene polymorphism: potential silencer motif and impact on progression in IgA nephropathy. Kidney Int, 49(2), 571-7, 1996.

Raskin, S, Cogan, J D, Summar, M L, Moreno, A, Krishnamani, M R, Phillips, J A. Genetic mapping of the human pituitary-specific transcriptional factor gene and its analysis in familial panhypopituitary dwarfism. Hum Genet, 98(6), 703-5, 1996.

Sierra-Rivera, E, Dasouki, M, Summar, M L, Krishnamani, M R, Meredith, M, Rao, P N, Phillips, J A, Freeman, M L. Assignment of the human gene (GLCLR) that encodes the regulatory subunit of gamma-glutamylcysteine synthetase to chromosome 1p21. Cytogenet Cell Genet, 72(2-3), 252-4, 1996.

Summar, M, Pietsch, J, Deshpande, J, Schulman, G. Effective hemodialysis and hemofiltration driven by an extracorporeal membrane oxygenation pump in infants with hyperammonemia. J Pediatr, 128(3), 379-82, 1996.

Ghishan, F K, Knobel, S M, Summar, M. Molecular cloning, sequencing, chromosomal localization, and tissue distribution of the human Na+/H+ exchanger (SLC9A2). Genomics, 30(1), 25-30, 1995.

Sierra-Rivera, E, Summar, M L, Dasouki, M, Krishnamani, M R, Phillips, J A, Freeman, M L. Assignment of the gene (GLCLC) that encodes the heavy subunit of gamma-glutamylcysteine synthetase to human chromosome 6. Cytogenet Cell Genet, 70(3-4), 278-9, 1995.

Summar, M L, Dasouki, M J, Schofield, P J, Krishnamani, M R, Vnencak-Jones, C, Tuchman, M, Mao, J, Phillips, J A. Physical and linkage mapping of human carbamyl phosphate synthetase I (CPS1) and reassignment from 2p to 2q35. Cytogenet Cell Genet, 71(3), 266-7, 1995.

Van Hove, J L, Kishnani, P, Muenzer, J, Wenstrup, R J, Summar, M L, Brummond, M R, Lachiewicz, A M, Millington, D S, Kahler, S G. Benzoate therapy and carnitine deficiency in non-ketotic hyperglycinemia. Am J Med Genet, 59(4), 444-53, 1995.

P??rez Jurado, LA, Phillips, JA, Summar, ML, Mao, J, Weber, JL, Schaefer, FV, Hazan, J, Argente, J. Genetic mapping of the human growth hormone-releasing factor gene (GHRF) using two intragenic polymorphisms detected by PCR amplification. Genomics, 20(1), 132-4, 1994.

Sierra-Rivera, E, Meredith, M J, Summar, M L, Smith, M D, Voorhees, G J, Stoffel, C M, Freeman, M L. Genes regulating glutathione concentrations in X-ray-transformed rat embryo fibroblasts: changes in gamma-glutamylcysteine synthetase and gamma-glutamyltranspeptidase expression. Carcinogenesis, 15(7), 1301-7, 1994.

Tiller, G E, Polumbo, P A, Summar, M L. Linkage mapping of the gene for type III collagen (COL3A1) to human chromosome 2q using a VNTR polymorphism. Genomics, 20(2), 275-7, 1994.

Spurr N.K., Cox S., Bryant S., Attwood J., Robson E., Shields D., Steinbrueck T., Jenkins T., Murray J., Kidd K., Summar M.L., Tsipouras P., Retief A., Druse T., Bale A., Vergnaud G., Weber J., McBride O.W., Donis-Keller H. and White R. The CEPH Consortium Linkage Map of Human Chromosome 2. Genomics, 14, 1055-1063, 1992.

Summar, M L. The use of linkage analysis and the Centre d'Etude Polymorphisme Humain (CEPH) panel of DNA in the study of the arginine vasopressin, oxytocin and prodynorphin gene loci. Prog Brain Res, 93, 309-17, 1992.

Tuchman, M, Mauer, S M, Holzknecht, R A, Summar, M L, Vnencak-Jones, C L. Prospective versus clinical diagnosis and therapy of acute neonatal hyperammonaemia in two sisters with carbamyl phosphate synthetase deficiency. J Inherit Metab Dis, 15(2), 269-77, 1992.

Henderson, GS, Conary, JT, Summar, M, McCurley, TL, Colley, DG. In vivo molecular analysis of lymphokines involved in the murine immune response during Schistosoma mansoni infection. I. IL-4 mRNA, not IL-2 mRNA, is abundant in the granulomatous livers, mesenteric lymph nodes, and spleens of infected mice. J Immunol, 147(3), 992-7, 1991.

Perry, S E, Summar, M L, Phillips, J A, Robertson, D. Linkage analysis of the human dopamine beta-hydroxylase gene. Genomics, 10(2), 493-5, 1991.

Summar, M L, Phillips, J A, Battey, J, Castiglione, C M, Kidd, K K, Maness, K J, Weiffenbach, B, Gravius, T C. Linkage relationships of human arginine vasopressin-neurophysin-II and oxytocin-neurophysin-I to prodynorphin and other loci on chromosome 20. Mol Endocrinol, 4(6), 947-50, 1990.

Summar, M L, Phillips, J A, Krishnamani, M R, Keefer, J, Trofatter, J, Schwartz, R C, Tsipouras, P, Willard, H, Ullrich, A. Protein kinase C: a new linkage marker for growth hormone and for COL1A1. Genomics, 5(1), 163-5, 1989.

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