The application is for the continued support of a Program Project Grant in one of the NICHD-funded Mental Retardation Research Centers. The program comprises five projects whose goal is better understanding of the biochemical defects and/or pathogenesis of a number of inborn errors which can result in mental retardation and/or early death. Conditions to be studied are glutaric acidemia types I and II, homocystinuria due to cystathionine beta-synthase deficiency and various defects of the mitochondrial respiratory chain. Drs. Goodman, Frerman and Kraus, the three BF Stolinsky Laboratories investigators, have common interests and goals, interact on a daily basis, use the same methods and equipment, and utilize common tissue culture and recombinant DNA cores of the MRRC. Dr. Neil Howell, at the University of Texas in Galveston, has been collaborating with us for several years, and brings longstanding expertise and interest in the biochemistry and molecular biology of the respiratory chain to the project. Project I is concerned with glutaric acidemia, a disorder which causes mental retardation and degeneration of the basal ganglia, and will examine functional domains of normal glutaryl-coenzyme A dehydrogenase as well as how normal function is perturbed by naturally occurring mutations. Projects II and IV focus on the biochemistry and molecular biology of glutaric acidemia type II (GA2), a disorder which causes early death and (often) congenital anomalies, examining the effect of mutations of two proteins (ETF and ETF:QO) whose deficiency causes it. Project III seeks to identify mutations of the mitochondrial genome in patients with Leber's Hereditary Optic Neuropathy (LHON) and selected neuromuscular disorders; and project V will examine genetic heterogeneity in patients with propionic acidemia and homocystinuria due to deficiency of cystathionine beta-synthase. All of these projects have the common goal of eventually understanding how disturbed enzyme function leads to disease, since such information is essential for formulating rational approaches to therapy.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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University of Colorado Denver
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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
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
Ravn, K; Chloupkova, M; Christensen, E et al. (2000) High incidence of propionic acidemia in greenland is due to a prevalent mutation, 1540insCCC, in the gene for the beta-subunit of propionyl CoA carboxylase. Am J Hum Genet 67:203-6

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