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Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency
Author(s) -
Segal Joanna,
Mülleder Michael,
Krüger Antje,
Adler Thure,
ScholzeWittler Manuela,
Becker Lore,
CalzadaWack Julia,
Garrett Lillian,
Hölter Sabine M.,
Rathkolb Birgit,
Rozman Jan,
Racz Ildiko,
Fischer Ralf,
Busch Dirk H.,
Neff Frauke,
Klingenspor Martin,
Klopstock Thomas,
Grüning NanaMaria,
Michel Steve,
LukaszewskaMcGreal Beata,
Voigt Ingo,
Hartmann Ludger,
Timmermann Bernd,
Lehrach Hans,
Wolf Eckhard,
Wurst Wolfgang,
GailusDurner Valérie,
Fuchs Helmut,
H. de Angelis Martin,
Schrewe Heinrich,
Yuneva Mariia,
Ralser Markus
Publication year - 2019
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1002/jimd.12105
Subject(s) - triosephosphate isomerase , biology , valine , mutation , enzyme assay , enzyme , isoleucine , biochemistry , medicine , amino acid , leucine , gene
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. TPI Ile170Val/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. TPI Ile170Val/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.