Triosephosphate isomerase deficiency: facts and doubts.
Many glycolytic enzymopathies have been described that manifest clinically as chronic hemolytic anemia. One of these, triosephosphate isomerase (TPI) deficiency, is unique among the glycolytic enzyme defects since it is associated with progressive neurological dysfunction and frequently with childhood death. The physiological function of TPI is to adjust the rapid equilibrium between dihydroxyacetone phosphate and glyceraldehyde-3-phosphate produced by aldolase in glycolysis, which is interconnected to the pentose phosphate pathway and to lipid metabolism via triosephosphates. The TPI gene is well characterized; structure and function studies suggest that instability of the isomerase due to different mutations of the enzyme may underlie the observed reduced catalytic activity. Patients with various inherited mutations have been identified. The most abundant mutation is a Glu104Asp missense mutation that is found in homozygotes and compound heterozygotes. Two germ-line identical Hungarian compound heterozygote brothers with distinct phenotypes question the exclusive role of the inherited mutations in the etiology of neurodegeneration. This paper: (i) reviews our present understanding of TPI mutation-induced structural alterations and their pathological consequences, (ii) summarizes the consequences of TPI impairment in the Hungarian case at local and system levels, and (iii) raises critical questions regarding the exclusive role of TPI mutations in the development of this human disease.
Orosz
Ferene
F
Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Budapest, Hungary.
Oláh
Judit
J
Ovádi
Judit
J
D000746:Anemia, Hemolytic, Congenital Nonspherocytic / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics*; D004912:Erythrocytes / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D014305:Triose-Phosphate Isomerase / Q000172:deficiency* / Q000235:genetics*
D014305:Triose-Phosphate Isomerase