A novel mutation of the fumarase gene in a family with autosomal recessive fumarase deficiency

Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte
Anne M RemesJ Kalervo Hiltunen

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.

Citations

Mar 30, 2011·Journal of Inherited Metabolic Disease·Sarah PicaudUdo Oppermann
Sep 13, 2005·Journal of Medical Genetics·H J LehtonenL A Aaltonen
Jun 16, 2010·Journal of Inherited Metabolic Disease·Gabriella AllegriMaria L Costa de Oliveira
Apr 7, 2016·Scientifica·Swati ChaturvediSudipta Saha
May 12, 2011·Human Mutation·Chris OttolenghiPascale de Lonlay
Mar 3, 2006·Molecular Genetics and Metabolism·M DeschauerF N Gellerich
Mar 4, 2008·Biochimica Et Biophysica Acta·Nuno RaimundoAnu Suomalainen
Apr 1, 2006·American Journal of Medical Genetics. Part a·Wen-Qi ZengVivian E Shih
Jun 9, 2006·American Journal of Physiology. Cell Physiology·Jean-Jacques BrièrePierre Rustin
Nov 21, 2019·American Journal of Medical Genetics. Part a·Olivia GrocottMelanie B Berkmen
Oct 15, 2020·Journal of Child Neurology·Marieke PeetsoldCacha Peeters

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