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Glutaric Acidemia Types I and II
Glutaric acidemias are recessively inherited human disorders characterized by the accumulation and excretion of glutaric acid. Glutaric acidemia type I (GAI) is due to deficiency of glutaryl-CoA dehydrogenase (GCDH), an FAD-containing enzyme of the mitochondrial matrix involved in the oxidation of lysine, We have cloned and expressed cDNAs that encode human GCDH and ETF:QO, and cDNAs that encode the human alpha and beta subunits of ETF have been cloned by others. We have identified several mutations in GAI and GAII patients, in some cases by examining GCDH, ETF and ETF:QO mRNA, and in others by examining the genes themselves. The method used to search for mutations is to amplify appropriate segments of mRNA or DNA by PCR (polymerase chain reaction), and to examine the products by methods sensitive enough to recognize even single base changes. We have expressed some of these mutations in bacteria and/or yeast, and are now examining in detail their effect on enzyme structure and function. Present directions are to continue mutation analysis on GAI and GAII patients, hoping in this way to build comprehensive structure-function maps of these proteins. We are also making transgenic models of GAI and GAII in mice, using the general method of gene knockout by homologous recombination in embryonic stem (ES) cells, to determine the precise relationships between genotype and phenotype. Selected Publications
Ojwang PJ, Pegoraro RJ, Deppe WM, Sankar R, McKerrow N, Varughese L, Stoker AF, Goodman SI. Biochemical and molecular diagnosis of glutaric aciduria type 1 in a black South African male child: case report. East Afr Med J. 2001 Dec;78(12):682-5. Wajne M, Vargas CR, Funayama C, Fernandez A, Elias ML, Goodman SI, Jakobs C, van der Knaap MS. D-2-Hydroxyglutaric aciduria in a patient with a severe clinical phenotype and unusual MRI findings. J Inherit Metab Dis. 2002 Feb;25(1):28-34. Koeller DM, Woontner M, Crnic LS, Kleinschmidt-DeMasters B, Stephens J, Hunt EL, Goodman SI. Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type I. Hum Mol Genet. 2002 Feb 15;11(4):347-57. Rao KS, Vander Velde D, Dwyer TM, Goodman SI, Frerman FE. Alternate substrates of human glutaryl-CoA dehydrogenase: structure and reactivity of substrates, and identification of a novel 2-enoyl-CoA product. Biochemistry. 2002 Jan 29;41(4):1274-84. Goodman SI. Prenatal diagnosis of glutaric acidemias. Prenat Diagn. 2001 Dec;21(13):1167-8. |
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hydroxylysine and tryptophan, and is characterized clinically by a progressive movement disorder with neuronal loss and gliosis in the basal ganglia. Glutaric acidemia type II (GAII) is due to an abnormality in electron transfer from the FAD of GCDH (and other flavoprotein dehydrogenases) to ubiquinone in the respiratory chain; in some patients this is due to deficiency of electron transfer flavoprotein (ETF) in the matrix, and in others it is due to deficiency of ETF: ubiquinone oxidoreductase (ETF:QO) in the inner mitochondrial membrane. Patients with the most severe forms of GAII, defining how these (and other) mutations cause enzyme deficiency, and determining how enzyme deficiency causes the disease manifestations.