title: Mutations in the AUH gene cause 3-methylglutaconic aciduria type I.
abstract: The conversion of 3-methylglutaconyl-CoA to 3-hydroxy-3-methylglutaryl-CoA is the only step in leucine catametabolism yet to be characterized at enzyme and DNA levels. The deficiency of the putative mitochondrial enzyme 3-methylglutaconyl-CoA hydratase associates with the rare organic aciduria 3-methylglutaconic aciduria type I (MGA1), but neither the enzyme nor its gene have been described in any organism. Here we report that human 3-methylglutaconyl-CoA hydratase is identical with a previously described RNA-binding protein (designated AUH) possessing enoyl-CoA hydratase activity. Molecular analyses in five patients from four independent families revealed homozygosity or compound heterozygosity for mutations in the AUH gene; most mutations are predicted to completely abolish protein function. Mutations identified include c.80delG, R197X, IVS8-1G>A, A240V, and c.613_614insA. Clinical severity of MGA1 in published patients has been quite variable. Included in the present study is an additional patient with MGA1 who was detected by neonatal screening and has remained asymptomatic up to his present age of 2 years. The boy is homozygous for an N-terminal frameshift mutation in the AUH gene. Complete absence of 3-methylglutaconyl-CoA hydratase/AUH appears to be compatible with normal development in some cases. Further work is required to identify external or genetic factors associated with development of clinical problems in patients with MGA1.
authors.affiliation: Department of General Paediatrics, Ruprecht-Karls-University, Heidelberg, Germany.
authors.forename: T B Nga
authors.initials: TB
authors.lastname: Ly
authors.forename: Verena
authors.initials: V
authors.lastname: Peters
authors.forename: K Michael
authors.initials: KM
authors.lastname: Gibson
authors.forename: Michael
authors.initials: M
authors.lastname: Liesert
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Buckel
authors.forename: Bridget
authors.initials: B
authors.lastname: Wilcken
authors.forename: Kevin
authors.initials: K
authors.lastname: Carpenter
authors.forename: Regina
authors.initials: R
authors.lastname: Ensenauer
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.forename: Johannes
authors.initials: J
authors.lastname: Zschocke
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000652:urine; D002331:Carnitine / Q000097:blood; D002675:Child, Preschool; D005091:Exons / Q000235:genetics; D005808:Genes, Recessive / Q000235:genetics; D005977:Glutarates / Q000652:urine*; D006801:Humans; D006836:Hydro-Lyases / Q000235:genetics*; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000097:blood / Q000235:genetics / Q000652:urine; D007805:Language Development Disorders / Q000097:blood / Q000235:genetics / Q000652:urine; D008297:Male; D009154:Mutation / Q000235:genetics*; D015997:Neonatal Screening / Q000379:methods
chemical_list: D005977:Glutarates; C022034:3-methylglutaconic acid; D006836:Hydro-Lyases; C035867:methylglutaconyl-CoA hydratase; D002331:Carnitine