title: A novel mutation of the fumarase gene in a family with autosomal recessive fumarase deficiency.
abstract: Fumarase hydratase (FH) deficiency is a rare familial disorder of the tricarboxylic acid cycle which is characterized by severe neurological impairment in early childhood. Several autosomal recessive mutations in the fumarate hydratase gene have been identified as a cause of the lack of fumarase activity in affected individuals. We describe a novel mutation in nucleotide 1127A>C of the fumarase cDNA which changes glutamine 376 to proline in the vicinity of the catalytic site and explains the loss of FH function. Two homozygous carriers of this mutation suffered from severe encephalopthy and died at a young age. Molecular modeling of FH structure shows that the mutation Gln376Pro in the second half of the fumarase sequence disrupts the structure of the active site. Analysis of the FH mutation and the mutant enzyme variant described here provides an explanation for the mechanism of FH deficiency at the molecular level and paves the way for the analysis of other dysfunctional FH variants.
authors.affiliation: Department of Neurology, University of Oulu, Oulu, Finland. anne.remes@oulu.fi
authors.forename: Anne M
authors.initials: AM
authors.lastname: Remes
authors.forename: Sirpa A
authors.initials: SA
authors.lastname: Filppula
authors.forename: Heikki
authors.initials: H
authors.lastname: Rantala
authors.forename: Jaakko
authors.initials: J
authors.lastname: Leisti
authors.forename: Aimo
authors.initials: A
authors.lastname: Ruokonen
authors.forename: Satyan
authors.initials: S
authors.lastname: Sharma
authors.forename: André H
authors.initials: AH
authors.lastname: Juffer
authors.forename: J Kalervo
authors.initials: JK
authors.lastname: Hiltunen
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D002648:Child; D002675:Child, Preschool; D005649:Fumarate Hydratase / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics*; D008969:Molecular Sequence Data; D017354:Point Mutation / Q000235:genetics*; D011487:Protein Conformation; D016415:Sequence Alignment
chemical_list: D005649:Fumarate Hydratase