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  Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase (TPI) deficiency

Segal, J., Mülleder, M., Krüger, A., Adler, T., Scholze-Wittler, M., Becker, L., et al. (2019). Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase (TPI) deficiency. Journal of Inherited Metabolic Disease, 2019, 1-11. doi:10.1002/jimd.12105.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0004-A672-0 Version Permalink: http://hdl.handle.net/21.11116/0000-0004-A673-F
Genre: Journal Article

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 Creators:
Segal, Joanna , Author
Mülleder, Michael, Author
Krüger, Antje , Author
Adler, Thure , Author
Scholze-Wittler, Manuela1, Author              
Becker, Lore, Author
Calzada-Wack, Julia , Author
Garrett, Lillian , Author
Hölter, Sabine M. , Author
Rathkolb, Birgit , Author
Rozman, Jan, Author
Racz, Ildiko , Author
Fischer, Ralf, Author
Busch, Dirk H. , Author
Neff, Frauke, Author
Klingenspor, Martin , Author
Klopstock, Thomas , Author
Grüning, Nana-Maria , Author
Michel, Steve , Author
Lukaszewska-McGreal, Beata2, Author              
Voigt, Ingo, AuthorHartmann, Ludger3, Author              Timmermann, Bernd4, Author              Lehrach, Hans5, Author              Wolf, Eckhard , AuthorWurst, Wolfgang, AuthorGailus-Durner, Valérie , AuthorFuchs, Helmut, Authorde Angelis, Martin H. , AuthorSchrewe, Heinrich1, Author              Yuneva, Mariia , AuthorRalser, Markus, Author more..
Affiliations:
1Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433548              
2Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Manuela B. Urban), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479669              
3Animal Unit (Head: Ludger Hartmann), Scientific Service (Head: Manuela B. Urban), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479665              
4Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              
5Emeritus Group of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385697              

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Free keywords: active site mutation; glycolytic enzymopathy; hemolytic anemia; protein stability disorder; site-directed mutagenesis; triosephosphate isomerase deficiency
 Abstract: Triosephosphate isomerase (TPI) deficiency is a fatal genetic disorder characterized by hemolytic anemia and neurological dysfunction. Although the enzyme defect in TPI was discovered in the 1960s, the exact etiology of the disease is still debated. Some aspects indicate the disease could be caused by insufficient enzyme activity, whereas other observations indicate it could be a protein misfolding disease with tissue-specific differences in TPI activity. We generated a mouse model in which exchange of a conserved catalytic amino acid residue (isoleucine to valine, Ile170Val) reduces TPI specific activity without affecting the stability of the protein dimer. TPIIle170Val/Ile170Val mice exhibit an approximately 85% reduction in TPI activity consistently across all examined tissues, which is a stronger average, but more consistent, activity decline than observed in patients or symptomatic mouse models that carry structural defect mutant alleles. While monitoring protein expression levels revealed no evidence for protein instability, metabolite quantification indicated that glycolysis is affected by the active site mutation. TPIIle170Val/Ile170Val mice develop normally and show none of the disease symptoms associated with TPI deficiency. Therefore, without the stability defect that affects TPI activity in a tissue-specific manner, a strong decline in TPI catalytic activity is not sufficient to explain the pathological onset of TPI deficiency.

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Language(s): eng - English
 Dates: 2019-04-242019-05-20
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1002/jimd.12105
PMID: 31111503
 Degree: -

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Title: Journal of Inherited Metabolic Disease
  Other : J. Inherit. Metab. Dis.
Source Genre: Journal
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Publ. Info: Lancaster, Eng. : MTP Press.
Pages: - Volume / Issue: 2019 Sequence Number: - Start / End Page: 1 - 11 Identifier: ISSN: 0141-8955
CoNE: https://pure.mpg.de/cone/journals/resource/954925471350