TPI1 – Triosephosphate Isomerase Deficiency

Triosephosphate isomerase 1 (TPI1) is an essential glycolytic enzyme, and pathogenic variants underlie the autosomal recessive metabolic disorder Triosephosphate Isomerase Deficiency. Clinically, affected individuals present with chronic nonspherocytic hemolytic anemia and progressive neuromuscular impairment, often leading to early childhood morbidity. Disease onset is typically in infancy, with laboratory findings of markedly reduced TPI activity across tissues. Pathogenic TPI1 variants perturb enzyme stability and dimerization, resulting in tissue‐specific enzyme deficiency and accumulation of toxic metabolites.

Inheritance is autosomal recessive, with over 30 alleles reported in more than 20 unrelated probands (PMID:8503454, PMID:9338582). The most common founder mutation, c.315G>C (p.Glu105Asp), accounts for 79% of mutated alleles in Northern European cohorts (PMID:9338582). Additional missense substitutions (e.g., c.721T>C (p.Phe241Leu)) and frameshift or nonsense variants have been identified in compound heterozygous and homozygous states across diverse populations.

The variant spectrum is dominated by missense mutations affecting highly conserved residues at the dimer interface or active site. To date, 11 missense, 1 nonsense, and multiple promoter or splicing mutations have been documented, with recurrent alleles such as p.Glu105Asp and p.Phe241Leu demonstrating founder effects. Frameshift alleles (e.g., c.366dup (p.Gly123fs)) further expand the mutational heterogeneity and correlate with severe enzyme deficiency.

Functional studies show that disease‐associated TPI1 proteins are thermolabile with reduced catalytic activity in erythrocyte lysates and abnormal microcompartmentalization (PMID:8503454). Yeast assays reveal that pathogenic variants primarily disrupt homodimerization rather than catalytic site function (PMID:17183658). Mouse models with isolated catalytic defects (Ile170Val) do not recapitulate clinical pathology, emphasizing the central role of stability defects in disease (PMID:31111503). Drosophila wstd hypomorphic mutants exhibit neuromuscular phenotypes mirroring human pathology, underscoring evolutionary conservation of the pathogenic mechanism (PMID:17008404).

Collectively, genetic and experimental evidence supports a Definitive gene‐disease relationship: autosomal recessive inheritance, segregation in multiple families, and concordant biochemical and model organism data. These insights inform diagnostic screening, genetic counseling, and emerging stability‐focused therapies. Key Take‐home: TPI1 pathogenic variants cause a clinically recognizable autosomal recessive disorder through enzyme instability, guiding molecular diagnosis and potential pharmacological rescue strategies.

References

• American journal of human genetics • 1993 • Human triosephosphate isomerase deficiency resulting from mutation of Phe-240. PMID:8503454
• Human mutation • 1997 • Evidence for founder effect of the Glu104Asp substitution and identification of new mutations in triosephosphate isomerase deficiency. PMID:9338582
• PloS one • 2006 • Triose phosphate isomerase deficiency is caused by altered dimerization--not catalytic inactivity--of the mutant enzymes. PMID:17183658
• Journal of inherited metabolic disease • 2019 • Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency. PMID:31111503
• Proceedings of the National Academy of Sciences of the United States of America • 2006 • wasted away, a Drosophila mutation in triosephosphate isomerase, causes paralysis, neurodegeneration, and early death. PMID:17008404

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