In a patient with ribose 5-phosphate isomerase deficiency (RPIAD; 608611) who presented with leukoencephalopathy and peripheral neuropathy (van der Knaap et al., 1999), Huck et al. (2004) identified compound heterozygosity for 2 mutations in the RPI gene: one, inherited from the mother, was a 1-bp deletion (540delG), resulting in a frameshift at codon 181 with a premature stop at codon 17 (Asn181fsTer17), a protein truncation of 196 amino acids; the other mutation, presumably inherited from the father, was a 182C-T transition, resulting in an ala61-to-val substitution (A61V; 180430.0002).
Wamelink et al. (2010) studied 2 cell lines, fibroblast and lymphoblast, derived from the patient with RPIA deficiency reported by van der Knaap et al. (1999) and Huck et al. (2004). Western blot and mass spectrometry analysis confirmed reduced RPIA levels in both cell lines, with lymphoblasts retaining about 30% residual levels of the protein and fibroblast levels falling below the level of detection. Similarly, mRNA levels showed a greater decrease in fibroblasts than in lymphoblasts; enzyme activity was not detectable in fibroblasts but was reduced to 28% of controls in lymphoblasts. The truncated version of the protein was not detected, indicating that it either is not expressed or is rapidly degraded. Studies in yeast showed that the A61V missense mutation had 30% residual activity when expressed at low levels but that it could complement RPIA loss when expressed at high levels. Metabolic changes in yeast expressing the mutant allele were similar to those observed in the patient. The findings indicated that reduced RPIA activity and reduced expression of the mutant protein contributed to the phenotype.
