Gerard Vockley, MD, PhD

  • Chief, Division of Medical Genetics
  • Cleveland Family Endowed Chair in Pediatric Research, University of Pittsburgh
  • Director, Center for Rare Disease Therapy
  • Professor of Pediatrics, University of Pittsburgh School of Medicine
  • Professor of Human Genetics, University of Pittsburgh Graduate School of Public Health

Education & Training

  • Graduate School – University of Pennsylvania – PhD – Genetics
  • Medical School – University of Pennsylvania – MD
  • Residency – University of Colorado Health Sciences Center – Pediatrics
  • Fellowship – Yale University School of Medicine – Pediatrics & Human Genetics

Research Grants

NIH Grants:  R01, R13

Research Summary

The acyl-CoA dehydrogenases (ACDs) are a family of 1 mitochondrial enzyme involved in fatty acid and amino acid metabolism which catalyze the transfer of electrons from various acyl-CoA esters to electron transfer flavoprotein. Biochemical and immunological studies have identified 11 distinct members of the ACD enzyme family, each with a narrow substrate specificity. Long, medium and short chain acyl-CoA dehydrogenases (LCAD, MCAD, and SCAD) catalyze the first step in the b-oxidation cycle with substrate optima of 16, 8 and 4 carbon chains, respectively. Isovaleryl-CoA dehydrogenase (IVD) and 2-methyl branched-chain acyl-CoA dehydrogenase (2-meBCAD) catalyze the third step in leucine and isoleucine/valine metabolism, respectively. Each mature enzyme is a homotetramer and each monomer contains a non-covalently bound flavin molecule (FAD) as a prosthetic group. Deficiencies of all these enzymes except 2-meBCAD have been shown to cause disease in humans. One of these conditions (MCAD deficiency) may be the most common inborn error of metabolism in humans. My laboratory focuses on the use of molecular genetic techniques to investigate the structure/function relationship in the ACD gene family at the molecular level and relate this information to mutations responsible for clinical deficiencies of these enzymes. Specific topics of interest in my lab include:

  1. analysis of the complex pathway of ACD maturation, focusing on the process of assembly of the enzymes
  2. expression analysis and computer-aided molecular modeling of mutant alleles from patients with deficiencies of these enzymes as a source of naturally occurring mutations of functional significance
  3. characterization of structure/function relationships important in the active site, tetramerization, and determination of substrate specificity
  4. novel therapy for deficiencies of these enzymes
  5. functional and structural interactions of the three major pathways of mitochondrial energy pathway, and 6) contribution of energy dysfunction to common disease.

The pathway of ACD maturation is studied by metabolic labeling of ACDs in tissue culture cells. Mutant alleles from patients with deficiencies of the ACDs are analyzed via eukaryotic and prokaryotic expression in order to characterize the biochemical and functional nature of the abnormal enzyme proteins produced by these patients' cells. Finally, we study mouse models for these disorders to use in developing gene therapy techniques. I have mentored numerous graduate and MD, PhD students, medical students, post-doctoral fellows, and junior faculty. I am the founder and continue to lead the Society for Metabolic Disorders North American Metabolic academy, a week-long course introduce the field of inborn errors of metabolis to medical genetics residents, and routinely teach in its European counterpart.

Representative Publications

  1. Wang Y, Mohsen AW, Mihalik SJ, Goetzman ES, Vockley J. (2010). Evidence for physical association of mitochondrial fatty acid oxidation and oxidative phosphorylation complexes. Journal of Biological Chemistry. 285: 29834-41.
  2. He M, Kratz LE, Michel JJ, Vallejo AN, Ferris L, Kelley RI, Hoover JJ, Jukic D, Gibson KM, Wolfe LA, Ramachandran D, Zwick ME, Vockley J. (2011). Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay. Journal of Clinical Investigation. 121: 976-84.
  3. Michaliszyn SF, Sjaarda LA, Mihalik SJ, Lee S, Bacha F, Chace DH, De Jesus VR, Vockley J, Arslanian SA. (2012). Metabolomic profiling of amino acids and beta-cell function relative to insulin sensitivity in youth. J Clin Endocrinol Metab. 97: E2119-24.
  4. Schiff M, Haberberger B, Xia C, Mohsen AW, Goetzman ES, Wang Y, Uppala R, Zhang Y, Karunanidhi A, Prabhu D, Alharbi H, Prochownik EV, Haack T, Haberle J, Munnich A, Rotig A, Taylor RW, Nicholls RD, Kim JJ, Prokisch H, Vockley J. (2015). Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency. Human Molecular Genetics. 24: 3238-47.
  5. Ghaloul-Gonzalez L, Goldstein A, Walsh Vockley C, Dobrowolski SF, Biery A, Irani A, Ibarra J, Morton DH, Mohsen AW, Vockley J. (2016). Mitochondrial respiratory chain disorders in the Old Order Amish population. Mol Genet Metab. 118: 296-303.
  6. Pan LA, Martin P, Zimmer T, Segreti AM, Kassiff S, McKain BW, Baca CA, Rengasamy M, Hyland K, Walano N, Steinfeld R, Hughes M, Dobrowolski SK, Pasquino M, Diler R, Perel J, Finegold DN, Peters DG, Naviaux RK, Brent DA, Vockley J. (2017). Neurometabolic Disorders: Potentially Treatable Abnormalities in Patients With Treatment-Refractory Depression and Suicidal Behavior. The American journal of psychiatry. 174: 42-50.
  7. Vockley J, Burton B, Berry GT, Longo N, Phillips J, Sanchez-Valle A, Tanpaiboon P, Grunewald S, Murphy E, Humphrey R, Mayhew J, Bowden A, Zhang L, Cataldo J, Marsden DL, Kakkis E. (2017). UX007 for the treatment of long chain-fatty acid oxidation disorders: Safety and efficacy in children and adults following 24weeks of treatment. Mol Genet Metab. 120: 370-7.
  8. Bloom K, Mohsen AW, Karunanidhi A, El Demellawy D, Reyes-Mugica M, Wang Y, Ghaloul-Gonzalez L, Otsubo C, Tobita K, Muzumdar R, Gong Z, Tas E, Basu S, Chen J, Bennett M, Hoppel C, Vockley J. (2018). Investigating the link of ACAD10 deficiency to type 2 diabetes mellitus. J Inherit Metab Dis. 41: 49-57.
  9. Seminotti B, Leipnitz G, Karunanidhi A, Kochersperger C, Roginskaya VY, Basu S, Wang Y, Wipf P, Van Houten B, Mohsen AW, Vockley J. (2018). Mitochondrial energetics is impaired in very long-chain acyl-CoA dehydrogenase deficiency and can be rescued by treatment with mitochondria-targeted electron scavengers. Human Molecular Genetics. In Press: .