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

Mirjam M C Wamelink1, Nana-Maria Grüning, Erwin E W Jansen

  • 1Department of Clinical Chemistry, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.

Journal of Molecular Medicine (Berlin, Germany)
|May 26, 2010
PubMed

Insights

Ribose 5-phosphate isomerase (RPI) deficiency, a rare disorder causing leukoencephalopathy, results from a combination of a non-functional RPI allele and a partially active one with expression deficits. This study clarifies the molecular basis of this rare genetic condition.

Area of Science:

  • Biochemistry
  • Genetics
  • Neuroscience

Background:

  • Ribose 5-phosphate isomerase (RPI) deficiency is an extremely rare enzymopathy of the pentose phosphate pathway.
  • It is characterized by progressive leukoencephalopathy and peripheral neuropathy.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying RPI deficiency.
  • To characterize patient-derived cell lines and develop a relevant model system.

Main Methods:

  • Analysis of patient-derived cell lines for RPI enzyme activity, concentration, and mRNA expression.
  • Development of a transgenic yeast model to study RPI deficiency.
  • Genetic analysis of patient alleles.

Main Results:

  • Patient-derived cell lines exhibited varying RPI enzyme activity, concentration, and mRNA expression.
  • The transgenic yeast model recapitulated metabolic and enzyme activity changes observed in the human syndrome.
  • Reduced RPI activity in patient cells was not solely due to the missense mutation (RPI(Ala61Val)).
  • RPI deficiency results from a null allele combined with a partially active allele exhibiting cell-type-dependent expression deficits.

Conclusions:

  • RPI deficiency is caused by compound heterozygosity for a null RPI allele and a hypomorphic allele with expression issues.
  • The complexity of these genetic and expression factors likely contributes to the extreme rarity of RPI deficiency.

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