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

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 (RPI(Ala61Val)) 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.