Stephen Goodman, M.D.
Inborn errors of amino, organic, and fatty acid metabolism
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, hydroxylysine and tryptophan, and is characterized clinically by a progressive movement disorder with neuronal loss and gliosis in the basal ganglia. Glutaric acidemia type 11 (GAII) is due to an abnormality in the transfer of electrons from the FAD of GCDH and similar enzymes to ubiquinone in the respiratory chain. In some patients GAII is due to deficiency of electron transfer flavoprotein (ETF) in the mitochondrial 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 develop renal cysts during fetal life and do not survive infancy. Research in this laboratory first established the causes of both these conditions, and is now aimed at identifying the mutations that cause them, determining how these mutations cause enzyme deficiency, and delineating how enzyme deficiency causes the clinical manifestations of disease.
We have cloned and expressed the 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. Many of these mutations have been expressed in bacteria and/or yeast, and we are now examining in detail their effect on enzyme structure and function.
Present directions are to extend our analysis of mutations found in GAI and GAII patients, and we hope in this way to build comprehensive structure-function maps of GCDH, ETF and ETF:QO and to understand how the mutations impair enzyme function and/or stability. We have also made a transgenic mouse model of GAI and are now characterizing its phenotype, with the ultimate aim of understanding how a defect in a single enzyme causes such specific and profound damage to a single area of the brain.
Publications
Goodman SI and Frerman FE (2001) Organic acidemias due to defects in lysine oxidation: 2-ketoadipic acidemia and glutaric acidemia, in The Metabolic and Molecular Bases of Inherited Disease (CR Scriver, AL Beaudet, WS Sly and D Valle, eds), 8th Edition, McGraw-Hill, New York, pp 2195-2204.
Frerman FE and Goodman SI (2001) Defects of electron transfer flavoprotein and electron transfer flavoprotein-ubiquinone oxidoreductase: Glutaric acidemia type II, in The Metabolic and Molecular Bases of Inherited Disease (CR Scriver, AL Beaudet, WS Sly and D Valle, eds), 8th Edition, McGraw-Hill, New York, pp 2357-2365.
Koeller DM, Woontner M, Crnic LS, Kleinschmidt-DeMasters B, Stephens J, Hunt EJ and Goodman SI: Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type I. Human Mol Genet 15;347-357, 2002.
Goodman SI, Binard RJ, Woontner MR and Frerman FE: Glutaric acidemia type II: Gene structure and mutations of the electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) gene. Molec Genet & Metab 77;86-90, 2002.
Treacy EP, Lee-Chong A, Roche G, Lynch B, Ryan S and Goodman S: Profound neurological presentation resulting from homozygosity for a mild glutaryl-CoA dehydrogenase mutation with a minimal biochemical phenotype. J Inherit Metab Dis 26;72-74, 2003.
Koeller DM, Sauer S, Wajner M, de Mello CF, Goodman SI, Woontner M, Muhlhausen C, Okun JG and Kolker S: Animal models for glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27;813-818, 2004.
Kolker S, Strauss KA, Goodman SI, Hoffmann GF, Okun JG, Koeller DM: Challenges
for basic research in glutaryl-CoA dehydrogenase deficiency. J Inherit
Metab Dis 27;843-849, 2004.
