Human Genetics

, Volume 115, Issue 2, pp 123–127 | Cite as

Mutations in the gene for the E1β subunit: a novel cause of pyruvate dehydrogenase deficiency

  • Ruth M. Brown
  • Rosemary A. Head
  • Ivan I. Boubriak
  • James V. Leonard
  • Neil H. Thomas
  • Garry K. BrownEmail author
Original Investigation


We describe two unrelated patients with pyruvate dehydrogenase (PDH) deficiency attributable to mutations in the gene encoding the E1β subunit of the complex. This is a previously unrecognised form of PDH deficiency, which most commonly results from mutations in the X-linked gene for the E1α subunit. Both patients had reduced immunoreactive E1β protein and both had missense mutations in the E1β gene. Activity of the PDH complex was restored in cultured fibroblasts from both patients by transfection and expression of the normal E1β coding sequence.


Lactic Acidosis Blood Lactate Concentration Y132C Mutation Maple Syrup Urine Disease Episodic Ataxia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank Dr. K. Downing and Dr. P. Biggin of the Department of Biochemistry, University of Oxford, for assistance with the structural analysis and protein graphics.


  1. Aral B, Benelli C, Ait Ghezala G, Amessou M, Fouque F, Maunoury C, Creau N, Kamoun P, Marsac C (1997) Mutations in PDX1, the human lipoyl-containing component X of the pyruvate dehydrogenase-complex gene on chromosome 11p1, in congenital lactic acidosis. Am J Hum Genet 61:1318–1326PubMedGoogle Scholar
  2. Brown GK, Otero LJ, LeGris M, Brown RM (1994) Pyruvate dehydrogenase deficiency. J Med Genet 31:875–879PubMedGoogle Scholar
  3. Brown RM, Otero LJ, Brown GK (1997) Transfection screening for primary defects in the pyruvate dehydrogenase E1alpha subunit gene. Hum Mol Genet 6:1361–1367PubMedGoogle Scholar
  4. Brown RM, Head RA, Brown GK (2002) Pyruvate dehydrogenase E3 binding protein deficiency. Hum Genet 110:187–191CrossRefPubMedGoogle Scholar
  5. Ciszak EM, Korotchkina LG, Dominiak PM, Sidhu S, Patel MS (2003) Structural basis for flip-flop action of thiamin pyrophosphate-dependent enzymes revealed by human pyruvate dehydrogenase. J Biol Chem 278:21240–21246CrossRefPubMedGoogle Scholar
  6. Edelmann L, Wasserstein MP, Kornreich R, Sansaricq C, Snyderman SE, Diaz GA (2001) Maple syrup urine disease: identification and carrier frequency determination of a novel founder mutation in the Ashkenazi Jewish population. Am J Hum Genet 69:863–868CrossRefPubMedGoogle Scholar
  7. Elpeleg ON, Ruitenbeek W, Jakobs C, Barash V, De Vivo DC, Amir N (1995) Congenital lactic acidemia caused by lipoamide dehydrogenase deficiency with favorable outcome. J Pediatr 126:72–74PubMedGoogle Scholar
  8. Fujii T, Garcia Alvarez MB, Sheu KF, Kranz Eble PJ, De Vivo DC (1996) Pyruvate dehydrogenase deficiency: the relation of the E1 alpha mutation to the E1 beta subunit deficiency. Pediatr Neurol 14:328–334CrossRefPubMedGoogle Scholar
  9. Gregersen N, Bross P, Jorgensen MM, Corydon TJ, Andresen BS (2000) Defective folding and rapid degradation of mutant proteins is a common disease mechanism in genetic disorders. J Inherit Metab Dis 23:441–447CrossRefPubMedGoogle Scholar
  10. Jolly C, Morimoto RI (2000) Role of the heat shock response and molecular chaperones in oncogenesis and cell death. J Natl Cancer Inst 92:1564–1572PubMedGoogle Scholar
  11. Lib M, Rodriguez-Mari A, Marusich MF, Capaldi RA (2003) Immunocapture and microplate-based activity measurement of mammalian pyruvate dehydrogenase complex. Anal Biochem 314:121–127CrossRefPubMedGoogle Scholar
  12. Lissens W, De Meirleir L, Seneca S, Liebaers I, Brown GK, Brown RM, Ito M, Naito E, Kuroda Y, Kerr DS, Wexler ID, Patel MS, Robinson BH, Seyda A (2000) Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Hum Mutat 15:209–219CrossRefPubMedGoogle Scholar
  13. Nellis MM, Danner DJ (2001) Gene preference in maple syrup urine disease. Am J Hum Genet 68:232–237CrossRefPubMedGoogle Scholar
  14. Patel MS, Roche TE (1990) Molecular biology and biochemistry of pyruvate dehydrogenase complexes. FASEB J 4:3224–3233PubMedGoogle Scholar
  15. Robinson BH (1995) Lactic acidemia (disorders of pyruvate carboxylase, pyruvate dehydrogenase). In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited disease, 7th edn. McGraw Hill, New York, pp 1479–1499Google Scholar
  16. Robinson BH, Chun K, Mackay N, Otulakowski G, Petrova-Benedict R, Willard H (1989) Isolated and combined deficiencies of the alpha-keto acid dehydrogenase complexes. Ann NY Acad Sci 573:337–346PubMedGoogle Scholar
  17. Shaag A, Saada A, Berger I, Mandel H, Joseph A, Feigenbaum A, Elpeleg ON (1999) Molecular basis of lipoamide dehydrogenase deficiency in Ashkenazi Jews. Am J Med Genet 82:177–182CrossRefPubMedGoogle Scholar
  18. Wicking CA, Scholem RD, Hunt SM, Brown GK (1986) Immunochemical analysis of normal and mutant forms of human pyruvate dehydrogenase. Biochem J 239:89–96PubMedGoogle Scholar
  19. Wynn RM, Chuang JL, Sansaricq C, Mandel H, Chuang DT (2001) Biochemical basis of type IB (E1beta) mutations in maple syrup urine disease. A prevalent allele in patients from the Druze kindred in Israel. J Biol Chem 276:36550–36556CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Ruth M. Brown
    • 1
  • Rosemary A. Head
    • 1
  • Ivan I. Boubriak
    • 1
  • James V. Leonard
    • 2
  • Neil H. Thomas
    • 3
  • Garry K. Brown
    • 1
    Email author
  1. 1.Genetics Unit, Department of BiochemistryUniversity of OxfordOxfordUK
  2. 2.Biochemistry, Endocrinology and Metabolism UnitInstitute of Child HealthLondonUK
  3. 3.Department of Paediatric NeurologySouthampton General HospitalSouthamptonUK

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