• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Jun 1994; 93(6): 2514–2518.
PMCID: PMC294471

Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency.

Abstract

We report an inborn error of the tricarboxylic acid cycle, fumarase deficiency, in two siblings born to first cousin parents. They presented with progressive encephalopathy, dystonia, leucopenia, and neutropenia. Elevation of lactate in the cerebrospinal fluid and high fumarate excretion in the urine led us to investigate the activities of the respiratory chain and of the Krebs cycle, and to finally identify fumarase deficiency in these two children. The deficiency was profound and present in all tissues investigated, affecting the cytosolic and the mitochondrial fumarase isoenzymes to the same degree. Analysis of fumarase cDNA demonstrated that both patients were homozygous for a missense mutation, a G-955-->C transversion, predicting a Glu-319-->Gln substitution. This substitution occurred in a highly conserved region of the fumarase cDNA. Both parents exhibited half the expected fumarase activity in their lymphocytes and were found to be heterozygous for this substitution. The present study is to our knowledge the first molecular characterization of tricarboxylic acid deficiency, a rare inherited inborn error of metabolism in childhood.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.1M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Wallace DC. Diseases of the mitochondrial DNA. Annu Rev Biochem. 1992;61:1175–1212. [PubMed]
  • Munnich A, Rustin P, Rötig A, Chretien D, Bonnefont JP, Nuttin C, Cormier V, Vassault A, Parvy P, Bardet J, et al. Clinical aspects of mitochondrial disorders. J Inherit Metab Dis. 1992;15(4):448–455. [PubMed]
  • Robinson BH. Cell culture studies on patients with mitochondrial diseases: molecular defects in pyruvate dehydrogenase. J Bioenerg Biomembr. 1988 Jun;20(3):313–323. [PubMed]
  • Remes AM, Rantala H, Hiltunen JK, Leisti J, Ruokonen A. Fumarase deficiency: two siblings with enlarged cerebral ventricles and polyhydramnios in utero. Pediatrics. 1992 Apr;89(4 Pt 2):730–734. [PubMed]
  • Elpeleg ON, Amir N, Christensen E. Variability of clinical presentation in fumarate hydratase deficiency. J Pediatr. 1992 Nov;121(5 Pt 1):752–754. [PubMed]
  • Edwards YH, Hopkinson DA. The genetic determination of fumarase isozymes in human tissues. Ann Hum Genet. 1979 Jan;42(3):303–313. [PubMed]
  • Akiba T, Hiraga K, Tuboi S. Intracellular distribution of fumarase in various animals. J Biochem. 1984 Jul;96(1):189–195. [PubMed]
  • Kobayashi K, Tuboi S. End group analysis of the cytosolic and mitochondrial fumarases from rat liver. J Biochem. 1983 Sep;94(3):707–713. [PubMed]
  • Suzuki T, Sato M, Yoshida T, Tuboi S. Rat liver mitochondrial and cytosolic fumarases with identical amino acid sequences are encoded from a single gene. J Biol Chem. 1989 Feb 15;264(5):2581–2586. [PubMed]
  • Wu M, Tzagoloff A. Mitochondrial and cytoplasmic fumarases in Saccharomyces cerevisiae are encoded by a single nuclear gene FUM1. J Biol Chem. 1987 Sep 5;262(25):12275–12282. [PubMed]
  • Van Someren H, Van Henegouwen HB, Westerveld A, Bootsma D. Synteny of the human loci for fumarate hydratase and udpg pyrophosphorylase with chromosome 1 markers in somatic cell hybrids. Cytogenet Cell Genet. 1974;13(6):551–557. [PubMed]
  • Tolley E, Craig I. Presence of two forms of fumarase (fumarate hydratase E.C. 4.2.1.2) in mammalian cells: immunological characterization and genetic analysis in somatic cell hybrids. Confirmation of the assignment of a gene necessary for the enzyme expression to human chromosome 1. Biochem Genet. 1975 Dec;13(11-12):867–883. [PubMed]
  • Suzuki T, Yoshida T, Tuboi S. Evidence that rat liver mitochondrial and cytosolic fumarases are synthesized from one species of mRNA by alternative translational initiation at two in-phase AUG codons. Eur J Biochem. 1992 Jul 15;207(2):767–772. [PubMed]
  • Kinsella BT, Doonan S. Nucleotide sequence of a cDNA coding for mitochondrial fumarase from human liver. Biosci Rep. 1986 Oct;6(10):921–929. [PubMed]
  • Gellera C, Uziel G, Rimoldi M, Zeviani M, Laverda A, Carrara F, DiDonato S. Fumarase deficiency is an autosomal recessive encephalopathy affecting both the mitochondrial and the cytosolic enzymes. Neurology. 1990 Mar;40(3 Pt 1):495–499. [PubMed]
  • Walker V, Mills GA, Hall MA, Millward-Sadler GH, English NR, Chalmers RA. A fourth case of fumarase deficiency. J Inherit Metab Dis. 1989;12(3):331–332. [PubMed]
  • Tanaka K, West-Dull A, Hine DG, Lynn TB, Lowe T. Gas-chromatographic method of analysis for urinary organic acids. II. Description of the procedure, and its application to diagnosis of patients with organic acidurias. Clin Chem. 1980 Dec;26(13):1847–1853. [PubMed]
  • Chretien D, Bourgeron T, Rötig A, Munnich A, Rustin P. The measurement of the rotenone-sensitive NADH cytochrome c reductase activity in mitochondria isolated from minute amount of human skeletal muscle. Biochem Biophys Res Commun. 1990 Nov 30;173(1):26–33. [PubMed]
  • Bourgeron T, Chretien D, Amati P, Rötig A, Munnich A, Rustin P. Expression of respiratory chain deficiencies in human cultured cells. Neuromuscul Disord. 1993 Sep-Nov;3(5-6):605–608. [PubMed]
  • Bourgeron T, Chretien D, Rötig A, Munnich A, Rustin P. Fate and expression of the deleted mitochondrial DNA differ between human heteroplasmic skin fibroblast and Epstein-Barr virus-transformed lymphocyte cultures. J Biol Chem. 1993 Sep 15;268(26):19369–19376. [PubMed]
  • Acuña G, Ebeling S, Hennecke H. Cloning, sequencing, and mutational analysis of the Bradyrhizobium japonicum fumC-like gene: evidence for the existence of two different fumarases. J Gen Microbiol. 1991 Apr;137(4):991–1000. [PubMed]
  • Woods SA, Miles JS, Roberts RE, Guest JR. Structural and functional relationships between fumarase and aspartase. Nucleotide sequences of the fumarase (fumC) and aspartase (aspA) genes of Escherichia coli K12. Biochem J. 1986 Jul 15;237(2):547–557. [PMC free article] [PubMed]
  • Miles JS, Guest JR. Complete nucleotide sequence of the fumarase gene fumA, of Escherichia coli. Nucleic Acids Res. 1984 Apr 25;12(8):3631–3642. [PMC free article] [PubMed]
  • Sacchettini JC, Frazier MW, Chiara DC, Banaszak LJ, Grant GA. Amino acid sequence of porcine heart fumarase. Biochem Biophys Res Commun. 1988 May 31;153(1):435–440. [PubMed]
  • Burgeois M, Goutieres F, Chretien D, Rustin P, Munnich A, Aicardi J. Deficiency in complex II of the respiratory chain, presenting as a leukodystrophy in two sisters with Leigh syndrome. Brain Dev. 1992 Nov;14(6):404–408. [PubMed]
  • Rivner MH, Shamsnia M, Swift TR, Trefz J, Roesel RA, Carter AL, Yanamura W, Hommes FA. Kearns-Sayre syndrome and complex II deficiency. Neurology. 1989 May;39(5):693–696. [PubMed]
  • Bonnefont JP, Chretien D, Rustin P, Robinson B, Vassault A, Aupetit J, Charpentier C, Rabier D, Saudubray JM, Munnich A. Alpha-ketoglutarate dehydrogenase deficiency presenting as congenital lactic acidosis. J Pediatr. 1992 Aug;121(2):255–258. [PubMed]
  • Zinn AB, Kerr DS, Hoppel CL. Fumarase deficiency: a new cause of mitochondrial encephalomyopathy. N Engl J Med. 1986 Aug 21;315(8):469–475. [PubMed]
  • Petrova-Benedict R, Robinson BH, Stacey TE, Mistry J, Chalmers RA. Deficient fumarase activity in an infant with fumaricacidemia and its distribution between the different forms of the enzyme seen on isoelectric focusing. Am J Hum Genet. 1987 Mar;40(3):257–266. [PMC free article] [PubMed]
  • Seid RC, Jr, Sakmar TP. A differential labelling model for determining the number of catalytically essential carboxyl groups in fumarase. Biochim Biophys Acta. 1981 Dec 15;662(2):196–201. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • Gene
    Gene
    Gene links
  • Gene (nucleotide)
    Gene (nucleotide)
    Records in Gene identified from shared sequence links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene
    HomoloGene links
  • MedGen
    MedGen
    Related information in MedGen
  • Nucleotide
    Nucleotide
    Published Nucleotide sequences
  • OMIM
    OMIM
    OMIM record citing PubMed
  • Pathways + GO
    Pathways + GO
    Pathways, annotations and biological systems (BioSystems) that cite the current article.
  • Protein
    Protein
    Published protein sequences
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...