Alternative titles; symbols
HGNC Approved Gene Symbol: RPIA
SNOMEDCT: 124667004;
Cytogenetic location: 2p11.2 Genomic coordinates (GRCh38): 2:88,691,673-88,750,929 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p11.2 | Ribose 5-phosphate isomerase deficiency | 608611 | Autosomal recessive | 3 |
The RPI gene encodes ribose 5-phosphate isomerase A (EC 5.3.1.6), an enzyme in the pentose phosphate pathway, which is an alternative route for the oxidation of hexoses (Apel et al., 1995).
Spencer and Hopkinson (1980) found evidence that ribose 5-phosphate isomerase is determined by a single structural locus and is probably a dimer. They detected no allelic variation in over 200 unrelated persons.
By exon trapping, Apel et al. (1995) identified the mouse Rpi gene downstream from the Igk locus. The predicted protein showed 53% sequence identity to the ribose 5-phosphate isomerase A of E. coli. Using the mouse Rpi cDNA as a probe in a human cDNA library of the Burkitt lymphoma cell line Raji, Apel et al. (1995) cloned human RPI. The deduced human and mouse proteins share 93% sequence identity. Northern blot analysis of mouse tissues detected a 1.8-kb transcript with a similar level of expression in all tissues tested except testis, which showed higher expression.
Gross (2019) mapped the RPIA gene to chromosome 2p11.2 based on an alignment of the RPIA sequence (GenBank BC015529) with the genomic sequence (GRCh38).
In a patient who presented with leukoencephalopathy and peripheral neuropathy (van der Knaap et al., 1999), Huck et al. (2004) identified deficiency of ribose 5-phosphate isomerase (RPIAD; 608611). Sequence analysis of the RPIA gene demonstrated a frameshift (180430.0001) and a missense (180430.0002) mutation.
By whole-exome sequencing in a child with RPIAD, Mahler et al. (2019) identified homozygosity for a missense mutation (W209C; 180430.0002) in the RPIA gene.
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.
For discussion of the ala61-to-val (A61V) mutation in the RPIA gene that was found in compound heterozygous state in a patient with ribose 5-phosphate isomerase deficiency (RPIAD; 608611) by Huck et al. (2004), see 180430.0001.
In a child with ribose 5-phosphate isomerase deficiency (RPIAD; 608611), Mahler et al. (2019) identified homozygosity for a c.627G-C transversion in the RPIA gene, resulting in a trp209-to-cys (W209C) substitution.
Apel, T. W., Scherer, A., Adachi, T., Auch, D., Ayane, M., Reth, M. The ribose 5-phosphate isomerase-encoding gene is located immediately downstream from that encoding murine immunoglobulin kappa. Gene 156: 191-197, 1995. [PubMed: 7758956] [Full Text: https://doi.org/10.1016/0378-1119(94)00901-4]
Gross, M. B. Personal Communication. Baltimore, Md. 6/24/2019.
Huck, J. H. J., Verhoeven, N. M., Struys, E. A., Salomons, G. S., Jakobs, C., van der Knaap, M. S. Ribose-5-phosphate isomerase deficiency: new inborn error in the pentose phosphate pathway associated with a slowly progressive leukoencephalopathy. Am. J. Hum. Genet. 74: 745-751, 2004. [PubMed: 14988808] [Full Text: https://doi.org/10.1086/383204]
Mahler, E. A., Johannsen, J., Tsiakas, K., Kloth, K., Luttgen, S., Muhlhausen, C., Alhaddad, B., Haack, T. B., Strom, T. M., Kortum, F., Meitinger, T., Muntau, A. C., Santer, R., Kubisch, C., Lessel, D., Denecke, J., Hempel, M. Exome sequencing in children. Dtsch. Arztebl. Int. 116: 197-204, 2019. [PubMed: 31056085] [Full Text: https://doi.org/10.3238/arztebl.2019.0197]
Spencer, N., Hopkinson, D. A. Biochemical genetics of the pentose phosphate cycle: human ribose 5-phosphate isomerase (RPI) and ribulose 5-phosphate 3-epimerase (RPE). Ann. Hum. Genet. 43: 335-342, 1980. [PubMed: 7396409] [Full Text: https://doi.org/10.1111/j.1469-1809.1980.tb01567.x]
van der Knaap, M. S., Wevers, R. A., Struys, E. A., Verhoeven, N. M., Pouwels, P. J. W., Engelke, U. F. H., Feikema, W., Valk, J., Jakobs, C. Leukoencephalopathy associated with a disturbance in the metabolism of polyols. Ann. Neurol. 46: 925-928, 1999. [PubMed: 10589548] [Full Text: https://doi.org/10.1002/1531-8249(199912)46:6<925::aid-ana18>3.0.co;2-j]
Wamelink, M. M. C., Gruning, N.-M., Jansen, E. E. W., Bluemlein, K., Lehrach, H., Jakobs, C., Ralser, M. The difference between rare and exceptionally rare: molecular characterization of ribose 5-phosphate isomerase deficiency. J. Molec. Med. 88: 931-939, 2010. [PubMed: 20499043] [Full Text: https://doi.org/10.1007/s00109-010-0634-1]