Journal of Molecular Medicine

, Volume 88, Issue 9, pp 931–939 | Cite as

The difference between rare and exceptionally rare: molecular characterization of ribose 5-phosphate isomerase deficiency

  • Mirjam M. C. Wamelink
  • Nana-Maria Grüning
  • Erwin E. W. Jansen
  • Katharina Bluemlein
  • Hans Lehrach
  • Cornelis Jakobs
  • Markus Ralser
Original article


Ribose 5-phosphate isomerase (RPI) deficiency is an enzymopathy of the pentose phosphate pathway. It manifests with progressive leukoencephalopathy and peripheral neuropathy and belongs, with one sole diagnosed case, to the rarest human disorders. The single patient was found compound heterozygous for a RPI frameshift and a missense (RPIAla61Val) allele. Here, we report that two patient-derived cell lines differ in RPI enzyme activity, enzyme concentration, and mRNA expression. Furthermore, we present a transgenic yeast model, which exhibits metabolite- and enzyme-activity changes that correspond to the human syndrome and show that the decrease in RPI activity in patient cells is not fully attributable to the residue exchange. Taken together, our results demonstrate that RPI deficiency is caused by the combination of a RPI null allele with an allele that encodes for a partially active enzyme which has, in addition, cell-type-dependent expression deficits. We speculate that a low probability for comparable traits accounts for the rareness of RPI deficiency.


Ribose 5-phosphate isomerase deficiency Rare metabolic disease Carbohydrate metabolism Pentose phosphate pathway 



We thank our colleagues for critical reading of the manuscript, Antje Krüger, Andreas Dahl, Mirjam Blattner, and Nada Kumer for help with RNA extraction and qPCRs, Serkan Ceyhan and Yvonne Himst for help with the sugar-phosphate determination and the enzyme assays, Beata Lukaszewska-McGreal for proteomic sample preparation, and the Max Planck Institute for Molecular Genetics for funding. We declare no competing interests.

Supplementary material

109_2010_634_MOESM1_ESM.pdf (192 kb)
ESM 1 (PDF 192 kb)


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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Mirjam M. C. Wamelink
    • 1
  • Nana-Maria Grüning
    • 2
  • Erwin E. W. Jansen
    • 1
  • Katharina Bluemlein
    • 2
  • Hans Lehrach
    • 2
  • Cornelis Jakobs
    • 1
  • Markus Ralser
    • 2
  1. 1.Department of Clinical ChemistryVU University Medical Center AmsterdamAmsterdamThe Netherlands
  2. 2.Max Planck Institute for Molecular GeneticsBerlinGermany

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