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Novel Mutations in the PC Gene in Patients with Type B Pyruvate Carboxylase Deficiency

  • Elsebet Ostergaard
  • Morten Duno
  • Lisbeth Birk Møller
  • H. Serap Kalkanoglu-Sivri
  • Ali Dursun
  • Didem Aliefendioglu
  • Helle Leth
  • Marianne Dahl
  • Ernst Christensen
  • Flemming Wibrand
Case Report
Part of the JIMD Reports book series (JIMD, volume 9)

Abstract

We have investigated seven patients with the type B form of pyruvate carboxylase (PC) deficiency. Mutation analysis revealed eight mutations, all novel. In a patient with exon skipping on cDNA analysis, we identified a homozygous mutation located in a potential branch point sequence, the first possible branch point mutation in PC. Two patients were homozygous for missense mutations (with normal protein amounts on western blot analysis), and two patients were homozygous for nonsense mutations. In addition, a duplication of one base pair was found in a patient who also harboured a splice site mutation. Another splice site mutation led to the activation of a cryptic splice site, shown by cDNA analysis.

All patients reported until now with at least one missense mutation have had the milder type A form of PC deficiency. We thus report for the first time two patients with homozygous missense mutations with the severe type B deficiency, clinically indistinguishable from other patients with type B form of PC deficiency.

The mutations found here are novel; it is noteworthy that four Turkish patients did not have any mutations in common, despite the rarity of PC deficiency. There is thus no evidence for recurrent mutations in the Turkish or other populations.

Notes

Acknowledgements

This work was supported by a grant from the Danish National Health Research Council.

References

  1. Carbone MA, MacKay N, Ling M, Cole DE, Douglas C, Rigat B, Feigenbaum A, Clarke JT, Haworth JC, Greenberg CR, Seargeant L, Robinson BH (1998 Jun) Amerindian pyruvate carboxylase deficiency is associated with two distinct missense mutations. Am J Hum Genet 62(6):1312–1319CrossRefPubMedCentralPubMedGoogle Scholar
  2. Carbone MA, Applegarth DA, Robinson BH (2002 Jul) Intron retention and frameshift mutations result in severe pyruvate carboxylase deficiency in two male siblings. Hum Mutat 20(1):48–56CrossRefPubMedGoogle Scholar
  3. Gao K, Masuda A, Matsuura T, Ohno K (2008 Apr) Human branch point consensus sequence is yUnAy. Nucleic Acids Res 36(7):2257–2267CrossRefPubMedCentralPubMedGoogle Scholar
  4. Hansen TL, Christensen E (1980) Studies on pyruvate carboxylase from cultured human fibroblasts and amniotic fluid cells. J Inherit Metab Dis 2(2):23–28CrossRefPubMedGoogle Scholar
  5. Marin-Valencia I, Roe CR, Pascual JM (2010 Sep) Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis. Mol Genet Metab 101(1):9–17CrossRefPubMedGoogle Scholar
  6. Monnot S, Serre V, Chadefaux-Vekemans B, Aupetit J, Romano S, De Lonlay P, Rival JM, Munnich A, Steffann J, Bonnefont JP (2009 May) Structural insights on pathogenic effects of novel mutations causing pyruvate carboxylase deficiency. Hum Mutat 30(5):734–740CrossRefPubMedGoogle Scholar
  7. Robinson BH (2001) Lactic acidemia: disorders of pyruvate carboxylase and pyruvate dehydrogenase. In: Scriver CR et al (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 2275–2296Google Scholar
  8. Schägger H, Cramer WA, von Jagow G (1994 Mar) Analysis of molecular masses and oligomeric states of protein complexes by blue native electrophoresis and isolation of membrane protein complexes by two-dimensional native electrophoresis. Anal Biochem 217(2):220–230CrossRefPubMedGoogle Scholar
  9. Singh R, Chénier D, Bériault R, Mailloux R, Hamel RD, Appanna VD (2005 Sep 30) Blue native polyacrylamide gel electrophoresis and the monitoring of malate- and oxaloacetate-producing enzymes. J Biochem Biophys Methods 64(3):189–199CrossRefPubMedGoogle Scholar
  10. Wexler ID, Kerr DS, Du Y, Kaung MM, Stephenson W, Lusk MM, Wappner RS, Higgins JJ (1998) Molecular characterization of pyruvate carboxylase deficiency in two consanguineous families. Pediat Res 43:579–584CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Elsebet Ostergaard
    • 1
  • Morten Duno
    • 1
  • Lisbeth Birk Møller
    • 2
  • H. Serap Kalkanoglu-Sivri
    • 3
  • Ali Dursun
    • 3
  • Didem Aliefendioglu
    • 4
  • Helle Leth
    • 5
  • Marianne Dahl
    • 6
  • Ernst Christensen
    • 1
  • Flemming Wibrand
    • 1
  1. 1.Department of Clinical GeneticsCopenhagen University Hospital RigshospitaletCopenhagenDenmark
  2. 2.Center of Applied Human Molecular GeneticsKennedy CenterGlostrupDenmark
  3. 3.Department of Pediatrics, Section of Nutrition & MetabolismHacettepe University Faculty of MedicineAnkaraTurkey
  4. 4.Department of Pediatrics, School of MedicineKirikkale UniversityKirikkaleTurkey
  5. 5.Department of PediatricsRoskilde University HospitalRoskildeDenmark
  6. 6.Department of PediatricsOdense University HospitalOdenseDenmark

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