Journal of Molecular Medicine

, Volume 82, Issue 8, pp 550–554 | Cite as

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

  • Anne M. RemesEmail author
  • Sirpa A. Filppula
  • Heikki Rantala
  • Jaakko Leisti
  • Aimo Ruokonen
  • Satyan Sharma
  • André H. Juffer
  • J. Kalervo Hiltunen
Original Article


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.


Fumarate hydratase Mutation Autosomal recessive 



Fumarate hydratase


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.


  1. 1.
    Someren H van, van Henegouven HB, Westerveld A, Bootsma D (1974) Synteny of the human loci for fumarate hydratase and UPDG pyrophosphorylase with chromosome 1 markers in somatic cell hybrids. Cytogenet Cell Genet 13:551–557PubMedGoogle Scholar
  2. 2.
    Tolley E, Craig J (1975) Presence of two forms of fumarase (fumarate hydratase EC in mammalian cells: immunological characterization and genetic analysis in somatic cell hybrids: conformation of the assignment of a gene necessary for the enzyme expression to human chromosome 1. Biochem Genet 13:866–883Google Scholar
  3. 3.
    Suzuki T, Salo M, Yoshida T, Tubri S (1989) Rat liver mitochondrial and cytosolic fumarases with identical amino acid sequences are encoded from a single gene. J Biol Chem 264:2581–2586PubMedGoogle Scholar
  4. 4.
    Kinsella BT Doonan S (1986) Nucleotide sequence of a cDNA coding for the mitochondrial fumarase from human liver. Biosci Rep 6:921–929PubMedGoogle Scholar
  5. 5.
    Zinn AB, Kerr DS, Hoppel CL (1986) Fumarase deficiency: a new cause of mitochondrial encephalopathy. N Engl J Med 315:469–475PubMedGoogle Scholar
  6. 6.
    Gellera C, Uziel G, Rimoldi M, Zeviani M, Laverda A, Carrara F, DiDonato S (1990) Fumarase deficiency in an autosomal recessive encephalopathy affecting both the mitochondrial and the cytosolic enzymes. Neurology 40:495–499PubMedGoogle Scholar
  7. 7.
    Remes AM, Rantala H, Hiltunen JK, Leisti J, Ruokonen A (1992) Fumarase deficiency: Two siblings with enlarged cerebral ventricles and polyhydramnions in utero. Pediatrics 89:730–734PubMedGoogle Scholar
  8. 8.
    Bourgeron T, Chretien D, Poggi-Bach J, Doonan S, Rabier D, Letouze P, Munnich A, Rotig A, Landrieu P, Rustin P (1994) Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency. J Clin Invest 2514–2518Google Scholar
  9. 9.
    Coughlin EM, Christensen E, Kunz PL, Krishnamoorthy KS, Walker V, Dennis NR, Chalmers RA, Elpeleg ON, Whelan D, Pollitt RJ, Ramesh V, Mandell R, Shih VE (1998) Molecular analysis and prenatal diagnosis of human fumarase deficiency. Mol Genet Metab 63:254–262CrossRefPubMedGoogle Scholar
  10. 10.
    Eng C, Kiuru M, Fernandez J, Aaltonen LA (2003) A role for mitochondrial enzymes in inherited neoplasia and beyond. Cancer 3:193–202CrossRefGoogle Scholar
  11. 11.
    Berendsen HJC, van der Spoel, D, van Drunen R (1995) GROMACS: A message-passing parallel molecular dynamics implementation. Comp Phys Commun 91:43–56CrossRefGoogle Scholar
  12. 12.
    Lindahl E, Hess B, van der Spoel D (2001) GROMACS 3.0: A package for molecular simulation and trajectory analysis. J Mol Model (Online) 7:306–317Google Scholar
  13. 13.
    Berendsen HJC, Postma JPM, van Gunsteren WF, Hermans J (1981) Interaction models for water in relation to protein hydration. In: Pullman B (ed) Intermolecular forces. Reidel, Dordrecht, pp 331–342Google Scholar
  14. 14.
    Darden T, York D, Pedersen L (1993) Particle mesh Ewald: An N-log (N) method for Ewald sums in large systems. J Chem Phys 103:10089–10092CrossRefGoogle Scholar
  15. 15.
    Hess B, Bekker H, Berendsen HJC, Fraaije JGEM (1997) LINCS: a linear constraint solver for molecular simulations. J Comp Chem 18:1463–1473CrossRefGoogle Scholar
  16. 16.
    Miyamoto S, Kollman PA (1992) SETTLE: an analytical version of the SHAKE and RATTLE algorithms for rigid water models. J Comp Chem 13:952–962Google Scholar
  17. 17.
    Tomlinson IPM, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Roylance RR, Olpin S, Bevan S, Barker K, Hearle N, Houlston RS, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, Vierimaa O, Aittomaki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Aaltonen LA, Multiple Leiomyoma Consortium (2002) Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 30:406–410PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Anne M. Remes
    • 1
    • 2
    Email author
  • Sirpa A. Filppula
    • 3
    • 4
  • Heikki Rantala
    • 5
  • Jaakko Leisti
    • 6
  • Aimo Ruokonen
    • 7
  • Satyan Sharma
    • 3
    • 4
  • André H. Juffer
    • 3
    • 4
  • J. Kalervo Hiltunen
    • 3
    • 4
  1. 1.Department of NeurologyUniversity of OuluOuluFinland
  2. 2.Department of Medical BiochemistryUniversity of OuluOuluFinland
  3. 3.Department of BiochemistryUniversity of OuluOuluFinland
  4. 4.BiocenterUniversity of OuluOuluFinland
  5. 5.Department of PediatricsUniversity of OuluOuluFinland
  6. 6.Department of Clinical GeneticsUniversity of OuluOuluFinland
  7. 7.Department of Clinical ChemistryUniversity of OuluOuluFinland

Personalised recommendations