{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T20:01:31Z","timestamp":1791489691926,"version":"4.3.4"},"reference-count":18,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 HD105311"],"award-info":[{"award-number":["R01 HD105311"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 HD104346"],"award-info":[{"award-number":["R01 HD104346"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["S10 OD028450"],"award-info":[{"award-number":["S10 OD028450"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"TPI Deficiency Research Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Triosephosphate Isomerase (TPI) is a glycolytic enzyme known to be associated with TPI deficiency, a severe form of childhood-onset glycolytic enzymopathy associated with hemolytic anemia, neuromuscular impairment and early death. Most often the disease results from the common TPI1E105D mutation, which can be either homozygous or compound heterozygous with another allele. Methods: We purified TPIR5G protein, studied mutant protein biochemistry, established and characterized TPIR5G\/f.s.patient cells, and investigated newly identified compounds for their efficacy in vitro using Western blot and TPI activity assays. Results: We identified novel TPI1 alleles that result in TPI Deficiency with an atypical presentation lacking anemia and with more slowly developing neurologic and locomotor impairment. The patient was found to be compound heterozygous with a missense mutation resulting in an R5G amino acid substitution and a frameshift mutation that is a predicted null allele. To better understand disease pathogenesis in this patient, we expressed and purified the TPIR5G human protein and studied it biochemically in addition to studying TPIR5G\/f.s.patient cells. We discovered that purified TPIR5G protein has wildtype activity with modestly increased dimer stability. We also discovered that steady-state TPI protein levels were markedly reduced, suggesting that the instability of the mutant protein underlies disease pathogenesis. We tested compounds recently identified in a screen for novel TPI Df therapies for their efficacy in TPIR5G\/f.s.patient cells. All three compounds significantly increased TPI protein levels in patient cells. As expected, since the mutant protein retains essentially wild type activity, the increase in TPI protein levels also resulted in a significant increase in TPI activity. Conclusions: These results establish TPIR5G as a TPI Df allele, demonstrate that reduced stability of the mutant protein underlies pathogenesis akin to other disease-causing alleles, and suggest that recently discovered developing therapies will likely function broadly and should be developed as potential TPI Df therapies.<\/jats:p>","DOI":"10.3390\/genes16101205","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T10:37:14Z","timestamp":1760438234000},"page":"1205","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Newly Identified TPI Deficiency Treatments Function for Novel Disease-Causing Allele, TPI1R5G"],"prefix":"10.3390","volume":"16","author":[{"given":"Joseph R.","family":"Figura","sequence":"first","affiliation":[{"name":"Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"},{"name":"Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3211-7815","authenticated-orcid":false,"given":"Presley","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"},{"name":"Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0037-8455","authenticated-orcid":false,"given":"Riley","family":"Sawka","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"},{"name":"Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maci","family":"Chambers","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"},{"name":"Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo","family":"Claudio","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"},{"name":"Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura L.","family":"Vollmer","sequence":"additional","affiliation":[{"name":"Department of Computational & Systems Biology, Organ Pathobiology and Therapeutics Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6846-9292","authenticated-orcid":false,"given":"Andreas","family":"Vogt","sequence":"additional","affiliation":[{"name":"Department of Computational & Systems Biology, Organ Pathobiology and Therapeutics Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3641-8153","authenticated-orcid":false,"given":"Gregg E.","family":"Homanics","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduard","family":"van Beers","sequence":"additional","affiliation":[{"name":"Department of Haematology, Center for Benign Haematology, Thrombosis and Haemostasis, University Medical Centre, 3511 ZK Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mylene","family":"Donge","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Unit, Department of Pediatrics, Centre Hospitalier de Luxembourg, L-1210 Luxembourg, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Scalais","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Unit, Department of Pediatrics, Centre Hospitalier de Luxembourg, L-1210 Luxembourg, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8008-9145","authenticated-orcid":false,"given":"Arthur","family":"Sorlin","sequence":"additional","affiliation":[{"name":"Service de G\u00e9n\u00e9tique Clinique, National Center of Genetics (NCG), Laboratoire National de Sant\u00e9, L-3555 Dudelange, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4306-3427","authenticated-orcid":false,"given":"Ariana J.","family":"Jou","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3424-4831","authenticated-orcid":false,"given":"Andrew P.","family":"VanDemark","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Palladino","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"},{"name":"Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1016\/j.bbadis.2009.09.012","article-title":"Triosephosphate isomerase deficiency: New insights into an enigmatic disease","volume":"1792","author":"Orosz","year":"2009","journal-title":"Biochim. 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