Contribution to Society

Providing researchers throughout the worldwide genomic community with access to genetic markers and techniques for rapid, large-scale genotyping efforts will contribute to rapid advances in the identification of genes and treatments associated with diseases in humans. In turn, these discoveries will lead to new preventions for inherited disorders.

Research Summary

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.

Recent Publications

Leppert MF and Singh NA (2003) NONSYNDROMIC SEIZURE DISORDERS: Epilepsy and the Use of the Internet to Advance Research. Ann Rev Genom. Vol. 4, pp. 437-457

Malhotra A, Peiffer AP, Ryujin DT, Elsner T, Kanner RE, Leppert MF, Hasstedt SJ (2003) Further evidence for the role of genes on chr2 and chr5 in the inheritance of pulmonary function. Am J Respir Crit Care Med. 168(5):556-61

Sandovici I, Leppert M, Hawk PR, Suarez A, Linares Y, Sapienza C (2003) Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions. Hum Mol Genet. 12(13):1569-1578.

Drayna D, Coon H, Kim UK, Elsner T, Cromer K, Otterud B, Baird L, Peiffer AP, Leppert M (2003) Genetic analysis of a complex trait in the Utah Genetic Reference Project: A major locus for PTC taste ability on chromosome 7q and a secondary locus on chromosome 16p. Hum Genet. 112(5-6):567-72.

Hall MA, Norman PJ, Thiel B, Tiwari H, Peiffer A, Vaughan RW, Prescott S, Leppert M, Schork NJ, Lanchbury JS (2002) Quantitative trait loci on chromosomes 1, 2, 3, 4, 8, 9, 11, 12 and 18 control variation in levels of T and B lymphocyte sub-populations. Am J Hum Genet. 70(5):1172-82.

Kim UK, Jorgenson E, Coon H, Leppert M, Risch N, Drayna D (2003) Positional cloning of the human quantitative trait locus underlying taste sensitivity to phenylthiocarbamide. Science 299(5610):1221-5

Coon H, Eckfeldt JH, Leppert MF, Myers RH, Arnett DK, Heiss G, Province MA, and Hunt SC (2002) A genome-wide screen reveals evidence for a locus on chromosome 11 influencing variation in LDL cholesterol in the NHLBI Family Heart Study. Hum Genet. 111(3):263-269.

Warren EH, Otterud BE, Linterman RW, Brickner AG, Engelhard VH, Leppert MF, Martin PJ, and Riddell SR (2002) Feasibility of using genetic linkage analysis to identify the genes encoding T cell-defined minor histocompatibility antigens. Tissue Antigens. 59(4):293-303.

Hunt SC, Ellison RC, Atwood LD, Pankow JS, Province MA, Leppert MF (2002) Genome scans for blood pressure and hypertension: the NHLBI Family Heart Study. Hypertension. 40(1):1-6.

Samowitz WS, Curtin K, Ma KN, Edwards S, Schaffer D, Leppert MF, Slattery ML (2002) Prognostic significance of p53 mutations in colon cancer at the population level. Int J Cancer. 99(4):597-602.

Bernstein PS, Leppert MF, Singh N, Dean M, Lewis RA, Lupski JR, Allikmets R, and Seddon JM. Genotype–phenotype analysis of ABCR variants in macular degeneration probands and siblings. Invest Ophthalmol Vis Sci. 43(2):466-473.

Swoboda KJ, Soong BW, McKenna C, Brunt ER, Litt M, Bale JF Jr, Ashizawa T, Bennet LB, Bowcock AM, Roach ES, Gerson D, Matsuura T, Heydemann PT, Nespeca MP, Jankovic J, Leppert MF, Ptacek LJ (2001) Paroxysmal dyskinesia and infantile convulsions. Clinical and linkage studies. Genes Chromosomes Cancer. 32(4):381-383.

Samowitz WS, Curtin K, Leppert MF, and Slattery ML (2001) Uncommon TGFBRI allele is not associated with increased susceptibility to colon cancer. Genes Chromosomes Cancer. 32(4):381-3.

Coon H, Leppert M, Eckfeldt JH, Oberman A, Myers RH, Peacock JM, Province MA, Hopkins PN, Heiss G (2001) Genome-wide linkage analysis of lipids in the HyperGEN Blood Pressure Study. Arteriscler Thromb Vac Biol. 21(12):1969-76.

Bernstein PS, Tammur J, Singh N, Hutchinson A, Dixon M, Pappas CM, Zabriskie NA, Zhang K, Petrukhin K, Leppert MF, and Allikmets R (2001) Diverse macular dystrophy phenotype caused by a novel complex mutation in the ELOVL4 gene. Invest Ophthalmol Vis Sci 42(13):3331-3336.

Feitosa M, Borecki IB, Rich SS, Arnett DK, Shlinsky P, Myers RH, Leppert MF, and Province MA (2002) Quantitative-trait loci influencing body mass index reside on chromosomes 7 and 13: The NHLBI Family Heart Study. Am J Hum Genet. 70(1):72-82.

Samowitz WS, Curtin K, Lin HH, Robertson MA, Schaffer D, Nichols M, Gruenthal K, Leppert MF, Slattery ML (2001) The colon cancer burden of genetically defined hereditary nonpolyposis colon cancer. Gastroenterology. 121(4):830-838.

Samowitz WS, Curtin K, Ma KN, Schaffer D, Coleman LW, Leppert M, and Slattery ML (2001) Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev. 10(9):917-23.

Flanigan KM, Coffeen CM, Sexton L, Stauffer D, Brunner S, and Leppert MF (2001) Genetic characterization of a large, historically significant Utah kindred with facioscapulohumeral dystrophy. Neuromuscular Disorders. 11:525-529.

Samowitz WS, Holden JA, Curtin K, Edwards SL, Walker AR, Lin HA, Robertson MA, Nichols MF, Gruenthal KM, Lynch BJ, Leppert MF, and Slattery ML (2001) Inverse relationship between microsatellite instability and K-ras and p53 gene alterations in colon cancer. Am J Pathol. 158(4):1517-24.

Slattery ML, Samowitz W, Ballard L, Schaffer D, Leppert M, and Potter JD (2001) A molecular variant of the APC gene at codon 1822: its association with diet, lifestyle, and risk of colon cancer. Cancer Res. 61(3):1000-4.

Scott BT, Bovill EG, Callas PW, Hasstedt SJ, Leppert MF, Valliere JE, Varvil TS, and Long GL (2001) Genetic screening of candidate genes for a prothrombotic interaction with type I protein C deficiency in a large kindred. Thromb Haemost. 85(1):82-7.

Slattery ML, Curtin K, Anderson K, Ma KN, Edwards S, Leppert M, Potter J, Schaffer D, and Samowitz WS (2000) Associations between dietary intake and Ki-ras mutations in colon tumors: a population-based study. Cancer Res. 60(24):6935-41.

Samowitz WS, Curtin K, Schaffer D, Robertson M, Leppert M, Slattery ML (2000) Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival: a population-based study. Cancer Epidemiol Biomarkers Prev. 9(11):1193-7.

Slattery ML, Curtin K, Anderson K, Ma KN, Ballard L, Edwards S, Schaffer D, Potter J, Leppert M, and Samowitz WS (2000) Associations between cigarette smoking, lifestyle factors, and microsatellite instability in colon tumors. J Natl Cancer Inst. 92(22):1831-1836.

Coon H, Myers RH, Borecki IB, Arnett DK, Hunt SC, Province MA, Djousse L, Leppert MF (2000) Replication of linkage of familial combined hyperlipidemia to chromosome 1q with additional heterogeneous effect of apolipoprotein A-I/C-III/A-IV locus : the NHLBI Family Heart Study. Arterioscler Thromb Vasc Biol. 20(10):2275-80.

Williams RR, Rao DC, Ellison RC, Arnett DK, Heiss G, Oberman A, Eckfeldt JH, Leppert MF, Province MA, Mockrin SC, and Hunt SC (2000) NHLBI Family Blood Program: Methodology and Recruitment in the HyperGEN Network. Ann Epidemiol 10(6):389-400.

Leppert M (2000) Novel K+ channel genes in benign familial neonatal convulsions. Epilepsia 41(8):1066-7.

Province MA, Boerwinkle E, Chakravarti A, Cooper R, Fornage M, Leppert M, Risch N, and Ranade K (2000) Lack of association of the angiotensinogen-6 polymorphism with blood pressure levels in the comprehensive NHLBI Family Blood Pressure Program. J Hypertens. 18(7):867-76.

Swoboda KJ, Soong B, McKenna C, Brunt ER, Litt M, Bale JF Jr, Ashizawa T, Bennett LB, Bowcock AM, Roach ES, Gerson D, Matsuura T, Heydemann PT, Nespeca MP, Jankovic J, Leppert MF, and Ptacek LJ (2000) Paroxysmal kinesigenic dyskinesia and infantile convulsions: clinical and linkage studies. Neurology. 55(2):224-30.

Danziger, RS, Pappas C, Barnitz C, Varvil T, Hunt SC and Leppert MF (2000) Evaluation of heterodimeric guanylyl cyclase genes as candidates for human hypertension. Journal of Hypertension. 18:263-366.

Hong Y, Leppert MF, Lin J, Hunt SC, Rich SS, Arnett DK, Myers RH, Eckfeldt J, Williams RR, Province MA (2000) No evidence of linkage between the very-low-density lipoprotein receptor gene and fasting serum insulin or homeostasis model assessment insulin resistance index: the NHLBI Family Heart Study. Metabolism 49(3):293-7.

Leppert M and Singh N (1999) Susceptibility genes in human epilepsy. Semin. Neurol. 19(4):397-405.

Slattery ML, Potter JD, Ma KN, Caan BJ, Leppert M, and Samowitz W (2000) Western diet, family history of colorectal cancer, NAT2, GSTM-1 and risk of colon cancer. Cancer Causes Control. 11(1):1-8.

Flanigan KM, Kerr L, Bromberg MB, Leonard C, Tsuruda J, Zhang P, Gonzalez-Gomez I, Cohn R, Campbell KP, and Leppert MF (2000) Congenital muscular dystrophy with rigid spine syndrome: a clinical, pathological, radiological, and genetic study. Ann Neurol. 47(2):152-61.

Bovill EG, Hasstedt SJ, Leppert MF, Long GL (1999) Hereditary thrombophilia as a model for multigenic disease. Thromb Haemost. 82(2):662-6.

Spirio L, Green J, Robertson J, Robertson M, Otterud B, Sheldon J, Howse E, Green R, Groden J, White R and Leppert MF (1999) The identical 5' splice-site acceptor mutation in five attenuated APC families from Newfoundland demonstrates a founder effect. Human Genetics 105:388-398.

Katsanis N, Lewis RA, Stockton DW, Mai PM, Baird L, Beales PL , Leppert M, and Lupski JR (1999) Delineation of the critical interval of Bardet-Biedl Syndrome 1 (BBS1) to a small region of 11q13, through linkage and haplotype analysis of 91 pedigrees. Am J Hum Genet 65(6):1672-1679.

Singh N, Charlier C, Peiffer A, Stauffer D, Melis R, Enoch MA, Goldman D, Rogers S, Anderson VE, and Leppert MF (1999) Genes for rare idiopathic generalized epilepsies: BFNC. Adv Neurol 79:341-50

Peiffer A, Thompson J, Otterud B, Varvil T, Pappas C, Barnitz C, Gruenthal K, Kuhn R and Leppert MF (1999) A locus for febrile seizures (FEB3) maps to chromosome 2q23-24. Ann Neurol. 46:671-678.

Coon H, Leppert MF, Kronenberg F, Province MA, Myers RH, Arnett DK, Eckfeldt JH, Heiss G, Williams RR, Hunt SC (1999) Evidence for a major gene accounting for mild elevation in LDL cholesterol: the NHLBI Family Heart Study. Ann Hum Genet 63( Pt 5):401-12.

Shroyer NF, Lewis RA, Allikmets R, Singh N, Dean M, Leppert M, and Lupski JR (1999) The rod photoreceptor ATP-binding cassette transporter gene, ABCR, and retinal disease: from monogenic to multifactorial. Vision Research. 39:2357-2544.

Slattery ML, Potter JD, Samowitz W, Schaffer D, Leppert M (1999) Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev. 8(6):513-8.

MacDougall M, Jeffords LG, Gu TT, Knight CB, Frei G, Reus BE, Otterud B, Leppert M, Leach RJ (1999) Genetic linkage of the dentinogenesis imperfecta type III locus to chromosome 4q. J Dent Res. 78 (6):1277-82.

Samowitz WS, Slattery ML, Potter JD, Leppert MF (1999) BAT-26 and BAT-40 instability in colorectal adenomas and carcinomas and germline polymorphisms. Am J Pathol. 154(6):1637-41.

Belcher HM, Shapiro BK, Leppert MF, Butz AM, Sellers S, Arch E, Kolodner K, Pulsifer M, Lears MK, Kaufmann WE (1999) Sequential neuromotor examination in children with intrauterine cocaine/polydrug exposure. Dev Med Child Neurol. 41(4):240-246.

Elbein SC, Hoffman MD, Teng K, Leppert MF, Hasstedt SJ (1999) A genome-wide search for type 2 diabetes susceptibility genes in Utah Caucasians. Diabetes 48(5):1175-82.

Peiffer A, Singh N, Leppert M, Dobyns WB, and Carey JC (1999) Microcephaly and simplified gyral pattern in six related children. Am J Med Genet. 84:137-144.

Numasawa T, Koga H, Ueyama K, Maeda S, Sakou T, Harata S, Leppert MF, and Inoue I (1999) Human retinoic X receptor beta: complete genomic sequence and mutation search for ossification of posterior longitudinal ligament of the spine. J Bone Miner Res. 14(4):500-8.

Leppert M and Singh N (1999) Benign familial neonatal epilepsy with mutations in two potassium channel genes. Curr Opin Neurol. 12(2):143-7.

Hunt SC, Province MA, Atwood LD, Sholinsky P, Lalouel J-M, Rao DC, Williams RR, and Leppert MF (1999) No linkage of the lipoprotein lipase locus to hypertension in Caucasians. J Hypertens. 17(1):39-43.

Hedera P, Rainier S, Alvarado D, Zhao X, Williamson J, Otterud B, Leppert MF, and Fink JK (1999) Novel locus for autosomal dominant hereditary spastic paraplegia, on chromosome 8q. Am J Hum Genet 64(2):563-9.

Hobbs MR, Pole AR, Pidwirny GN, Rosen IB, Zarbo RJ, Coon H, Heath H 3rd, Leppert MF, and Jackson CE (1999) Hyperparathyroidism-jaw tumor syndrome: the HRPT2 locus is within a 0.7-cM region on chromosome 1q. Am J Hum Genet. 64(2):518-25.

Lewis RA, Shroyer NF, Singh N, Allikmets R, Hutchinson A, Li Y, Lupski JR, Leppert M, Dean M. (1999) Genotype/phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. Am. J. Hum. Genet. 64(2):422-34.