A novel mutation of the fumarase gene in a family with autosomal recessive fumarase deficiency
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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.
KeywordsFumarate hydratase Mutation Autosomal recessive
Polymerase chain reaction
The authors thank Ms. Anja Heikkinen, Ms. Aila Holappa, and Ms. Irma Vuoti for their expert technical assistance; the Center of Scientific Computing (CSC) in Espoo, Finland, is acknowledged for providing the available computing power. This study was supported by grants from the Academy of Finland, the Sidgrid Juselius Foundation and the Maud Kuistila Foundation.
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