Mark Leppert, Ph.D.

An aim of our research group is to develop new and improved techniques for identifying genetic variations that confer predispositions to human disorders and traits. The ascertainment of families in which such variant genes are segregating is an important first step toward localizing the disease-related genes on specific chromosomes. The genealogical resources available at the University of Utah have enabled researchers in human genetics to identify extended families who can contribute such information. Localization of a variant gene predisposing to a disease is accomplished by finding a marker allele that is inherited along with the disease phenotype. However, as many common diseases in humans are complex in their phenotypic expression, and as several genes may be involved, often large numbers of related individuals have to be genotyped at many marker loci. This requirement has led our group to adapt technologies evolving from DNA sequence research to the problem of large-scale and rapid genotyping. We are using this genetic approach, coupled with positional cloning, to understand inherited forms of epilepsy, particularly a specific type in which intermittent seizures appear at birth and cease spontaneously within six months, and to understand inherited forms of macular degeneration, a common form of retinal eye disease.

Unprecedented efforts aimed at extensive phenotyping of Utah families as part of the Utah Genetic Reference Project have yielded successful progress toward identifying the genetic loci responsible for quantitative traits such as phenylthiocarbamide sensitivity and variation in levels of lymphocyte subpopulations. These same families were utilized for the construction of the haplotype map for the International HapMap Project, which will readily facilitate the discovery of allelic variants responsible for common diseases.

Li Y, Liao W, Cargill M, Chang M, Matsunami N, Feng BJ, Poon A, Callis-Duffin KP, Catanese JJ, Bowcock AM, Leppert MF, Kwok PY, Krueger GG, Begovich AB. Carriers of rare missense variants in IFiH1 are protected from psoriasis. J Invest Dermatol. 2010 Jul 29. PMID20668468

Neklason DW, Tuohy TM, Stevens J, Otterud B, Baird L, Kerber RA, Samowitz WS, Kuwada SK, Leppert MF, Burt RW. Colorectal adenomas and cancer link to chromosome 13q22.1-13q31.3 in a family with excess colorectal cancer. J Med Genet. 2010 Jun 3. PMID20522424

McClay JL, Adkins DE, Isern NG, O’Connell TM, Wooten JB, Zedler BK, Dasika MS, Webb BT, Webb-Robertson BJ, Pounds JG, Murrelle EL, Leppert MF, van den Oord EJ. (1)H Nuclear magnetic resonance metabolomics analysis identifies novel urinary biomarkers for lung function. J Proteome Res. 2010 May 3. PMID20408573

Watkins WS, Rohrwasser A, Peiffer A, Leppert MF, Lalouel J-M, Jorde LB. AGT genetic variation, plasma AGT, and blood pressure: An analysis of the Utah Genetic Reference Project Pedigrees. Am J Hypertens. 2010 Apr 22. PMID20414195

Devanarayan V, Scholand MB, Hoidal J, Leppert MF, Crackower MA, O’Neill GP, Gervais FG. Identification of distinct plasma biomarker signatures in patients with rapid and slow declining forms of COPD. COPD. 2010. Feb;7(1):51-8. PMID20214463

Bleakley M, Otterud BE, Richardt JL, Mollerup AD, Hudecek M, Nishida T, Chaney CN, Warren EH, Leppert MF, Riddell SR. Leukemia-associated minor histocompatibility antigen discovery using T-cell clones isolated by in vitro stimulation of naïve CD8+ Tcells. Blood. 2010. Mar 4. PMID20203263

Kumanovics A, Wittwer CT, Pryor RJ, Augustine NH, Leppert MF, Carey JC, Ochs HD, Wedgwood RJ, Faville RJ Jr, Quie PG, Hill HR. Rapid molecular analysis of the STAT3 gene in job syndrome of hyper-IgE and recurrent infectious diseases. J Mol Diagn. 2010. Mar;12(2):213-9. PMID20093388

Bleyl SB, Saijoh Y, Bax NA, Gittenberger-de Groot AC, Wisse LJ, Chapman SC, Hunter J, Shiratori H, Hamada H, Yamada S, Shiota K, Klewer SE, Leppert MF, Schoenwolf GC. Dysregulation of the PDGFRA gene causes inflow tract anomalies including TAPVR: integrating evidence from human genetics and model organisms. Hum Mol Genet. 2010. Apr 1;19(7):1286-307 PMID20071345

North KE, Franceschini N, Avery CL, Baird L, Graff M, Leppert M, Chung JH, Zhang J, Hanis C, Boerwinkle E, Volcik KA, Grove ML, Mosley TH, Gu C, Heiss G, Pankow JS, Couper DJ, Ballantyne CM, Linda Kao WH, Weder AB, Cooper RS, Ehret GB, O’Connor AA, Chakravarti A, Hunt SC. Variation in the checkpoint kinase 2 gene is associated with type 2 diabetes in multiple populations. Acta Diabetol. 2009. Oct 24. PMID19855918

Knight S, Coon H, Johnson M, Leppert MF, Camp NJ, McMahon WM. Linkage analysis of Tourette syndrome in a large Utah pedigree. Tourette Syndrome Association International Consortium for Genetics. Am J Med Genet B Neuropsychiatr Genet. 2010. Mar 5;153B(2):656-62 PMID19777563