This is a revised application for continued support of a Program Project Grant in an NICHD-funded Mental Retardation Research Centers. The program, whose goal is to better understand the biochemical defects and pathogenesis of several inborn errors that can cause mental retardation, developmental disability and/or early death, comprises five projects. Disorders to be studied are glutaric acidemia types I and II, homocystinuria due to cystathionine beta-synthase deficiency,a nd propionic acidemia. The investigators, Drs Goodman, Frerman, Kraus and Koeller, have contiguous laboratories in the MRRC; share interests, methods and equipment; and interact closely on a daily basis. The project by Goodman is on glutaric acidemia type I (GAI), a disorder which causes mental retardation and striatal degeneration, and examines the mutations that cause GAI, the relationship between specific mutations and the biochemical and clinical phenotype, and structure-function aspects of glutaryl-coenzyme A dehydrogenase (GCDH), the enzyme whose deficiency causes the disease. Projects by Frerman and Goodman, focus on the biochemistry, molecular biology, and mutations of electron transfer flavoprotein (ETF) and ETF:ubiquinone oxidoreductase (ETF:QO), seeking to determine why mutations cause enzyme deficiency, and why enzyme deficiency causes clinical manifestations of glutaric acidemia type II (GA2). In this vein, the project by Goodman,also seeks to create a murine model of ETF:QO deficiency. The project by Kraus examines the biochemistry an molecular biology of cystathionine beta-synthase (CBS) and genotype-phenotype aspects of human CBS deficiency; and the project by Kraus examines propionyl-CoA carboxylase (PCC) and human PCC deficiency. The thread that unites these projects is the attempt to delineate why impaired enzyme function causes disease, information that is essential to formulate rational approaches to therapy.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD008315-23
Application #
2888795
Study Section
Mental Retardation Research Committee (HDMR)
Program Officer
Oster-Granite, Mary Lou
Project Start
1979-04-01
Project End
2000-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
23
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Fielding, Alistair J; Usselman, Robert J; Watmough, Nicholas et al. (2008) Electron spin relaxation enhancement measurements of interspin distances in human, porcine, and Rhodobacter electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO). J Magn Reson 190:222-32
Jiang, Hua; Rao, K Sudhindra; Yee, Vivien C et al. (2005) Characterization of four variant forms of human propionyl-CoA carboxylase expressed in Escherichia coli. J Biol Chem 280:27719-27
Moat, Stuart J; Bao, Liming; Fowler, Brian et al. (2004) The molecular basis of cystathionine beta-synthase (CBS) deficiency in UK and US patients with homocystinuria. Hum Mutat 23:206
Chloupkova, Maja; Reaves, Scott K; LeBard, Linda M et al. (2004) The mitochondrial ABC transporter Atm1p functions as a homodimer. FEBS Lett 569:65-9
Chloupkova, Maja; LeBard, Linda S; Koeller, David M (2003) MDL1 is a high copy suppressor of ATM1: evidence for a role in resistance to oxidative stress. J Mol Biol 331:155-65
Chloupkova, Maja; Maclean, Kenneth N; Alkhateeb, Asem et al. (2002) Propionic acidemia: analysis of mutant propionyl-CoA carboxylase enzymes expressed in Escherichia coli. Hum Mutat 19:629-40
Jones, Patricia M; Tjoa, Susan; Fennessey, Paul V et al. (2002) Addition of quantitative 3-hydroxy-octadecanoic acid to the stable isotope gas chromatography-mass spectrometry method for measuring 3-hydroxy fatty acids. Clin Chem 48:176-9
Janosik, M; Oliveriusova, J; Janosikova, B et al. (2001) Impaired heme binding and aggregation of mutant cystathionine beta-synthase subunits in homocystinuria. Am J Hum Genet 68:1506-13
Chloupkova, M; Ravn, K; Schwartz, M et al. (2000) Changes in the carboxyl terminus of the beta subunit of human propionyl-CoA carboxylase affect the oligomer assembly and catalysis: expression and characterization of seven patient-derived mutant forms of PCC in Escherichia coli. Mol Genet Metab 71:623-32
Maclean, K N; Janosik, M; Oliveriusova, J et al. (2000) Transsulfuration in Saccharomyces cerevisiae is not dependent on heme: purification and characterization of recombinant yeast cystathionine beta-synthase. J Inorg Biochem 81:161-71

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