Jan P. Kraus Professor Pediatrics / Cell and Developmental Biology Ph.D., Basel University, 1972 UC D - Anschutz Medical Campus RC1-North, Room 4128 Mail Stop 8313 12801 East 17th Ave Aurora, CO 80045 Phone: 303-724-3812 Email: Jan.Kraus@ucdenver.edu

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Departmental Affiliations Cell and Developmental Biology Department of Pediatrics

Other Graduate Program Affiliations Biomedical Sciences Program (BSP) Human Medical Genetics Web Sites Kraus Laboratory Pediatrics, Clinical Genetics and Metabolism

Molecular Basis of Inherited Human Disease

My laboratory studies the molecular basis of two inherited disorders associated with deficiency of cystathionine ß-synthase (CBS) and propionyl CoA carboxylase (PCC). CBS is a crucial regulator of serum levels of the thrombogenic amino acid homocysteine (Hcy) and is crucial for the tissue specific biosynthesis of cysteine. CBS deficiency is the most common cause of homocystinuria, an inherited autosomal recessive metabolic disease that if untreated, causes skeletal abnormalities, dislocated optic lenses, mental retardation and a dramatically increased incidence of thromboembolic disease. Mildly elevated plasma Hcy in humans has also been identified as an independent risk factor for cardiovascular and thromboembolic disease. Increasing numbers of epidemiological studies are also finding an association between elevated Hcy and neurodegenerative disorders such as Alzheimer's and Parkinson's disease. The crucial role of CBS in the regulation of plasma Hcy has lead to increasing interest in the mechanisms that regulate this enzyme and the cellular consequences of its dysfunction. Currently, we are applying a range of approaches including functional genomics, transgenic mouse models, X-ray crystallography, molecular cell biology and protein biochemistry to investigate the etiology of the various disease states associated with elevated Hcy due to impaired CBS activity.

	FISH analysis showing 2 copies of the human CBS gene in a transgenic mouse nucleus.

PCC is a mitochondrial enzyme comprised of non-identical subunits encoded on different chromosomes. Deficiency of PCC causes propionic acidemia. This condition is an autosomal recessive trait that is often life threatening in neonates. Recent research has indicated that in certain populations the incidence of this disease is far higher than previous estimates. Our research in this area is focused on improving our understanding of the molecular mechanisms that underlie the highly variable correlation between genotype and phenotype in propionic acidemia. To this end, we have developed a recombinant expression system using molecular chaperones that allows us to assess the effects of specific mutations upon PCC function. Adaptation of this system for large-scale expression of the human PCC holoenzyme in E.coli will facilitate characterization of the PCC enzyme complex using both spectroscopic and X-ray diffraction studies. We are currently identifying the promoter regions of both PCC genes to elucidate how PCC activity is regulated and to perform a functional analysis of the sequences that determine basal promoter activity in the human PCC genes. Techniques employed include the use of reporter constructs in luciferase assays, site directed mutagenesis, mammalian tissue culture, immunohistochemistry, band shift analysis and DNA footprinting.

Selected Publications

Oliveriusova J, Kery V, Maclean KN, Kraus JP. Deletion mutagenesis of human cystathionine beta -synthase: Impact on activity, oligomeric status and S-adenosylmethionine regulation. J Biol Chem. 2002 Dec; 277(50):48386-94.

Levy HL, Vargas JE, Waisbren SE, Kurczynski TW, Roeder ER, Schwartz RS, Rosengren S, Prasad C, Greenberg CR, Gilfix BM, MacGregor D, Shih VE, Bao L, Kraus JP. Reproductive fitness in maternal homocystinuria due to cystathionine beta-synthase deficiency. J Inherit Metab Dis. 2002 Aug;25(4):299-314.

Ratnam S, Maclean KN, Jacobs RL, Brosnan ME, Kraus JP, Brosnan JT. Hormonal regulation of cystathionine Beta -synthase expression in liver. J Biol Chem. 2002 Nov 8;277(45):42912-8.

Stabler SP, Steegborn C, Wahl MC, Oliveriusova J, Kraus JP, Allen RH, Wagner C, Mudd SH. Elevated plasma total homocysteine in severe methionine adenosyltransferase I/III deficiency. Metabolism. 2002 Aug;51(8):981-8.

Gaustadnes M, Wilcken B, Oliveriusova J, McGill J, Fletcher J, Kraus JP, Wilcken DE. The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype-phenotype correlations and response to treatment. Hum Mutat. 2002 Aug;20(2):117-26.

Latest Publications in PubMed