Academic journal article Genetics

Drosophila Model of Human Inherited Triosephosphate Isomerase Deficiency Glycolytic Enzymopathy

Academic journal article Genetics

Drosophila Model of Human Inherited Triosephosphate Isomerase Deficiency Glycolytic Enzymopathy

Article excerpt

ABSTRACT

Heritable mutations, known as inborn errors of metabolism, cause numerous devastating human diseases, typically as a result of a deficiency in essential metabolic products or the accumulation of toxic intermediates. We have isolated a missense mutation in the Drosophila sugarkill (sgk) gene that causes phenotypes analogous to symptoms of triosephosphate isomerase (TPI) deficiency, a human familial disease, characterized by anaerobic metabolic dysfunction resulting from pathological missense mutations affecting the encoded TPI protein. In Drosophila, the sgk gene encodes the glycolytic enzyme TPI. Our analysis of sgk mutants revealed TPI impairment associated with reduced longevity, progressive locomotor deficiency, and neural degeneration. Biochemical studies demonstrate that mutation of this glycolytic enzyme gene does not result in a bioenergetic deficit, suggesting an alternate cause of enzymopathy associated with TPI impairment.

METABOLIC defects resulting from inherited disorders cause numerous human diseases. Glycolytic enzymopathies result from a disturbance in anaerobic metabolism; however, these diseases remain poorly understood. Familial triosephosphate isomerase (TPI) deficiency, an autosomal recessive disorder, has been reported in numerous pedigrees and results in anemia, neuromuscular wasting, and reduced longevity (SCHNEIDER et al. 1965; VALENTINE 1966). The relationship of anemia, neuromuscular degeneration, and glycolytic flux to disease pathogenesis is not clear, and an animal model that captures salient features of TPI deficiency has not been reported. Our studies demonstrate the utility of Drosophila sugarkill (sgk) mutants as a model of glycolytic enzymopathy.

TPI is a 26.5-kDa soluble protein responsible for the conversion of dihydroxyacetone phosphate into glyceraldehyde-3-phosphate in glycolysis (RIEDER and ROSE 1959). The protein's structure has been studied in yeast (ALBER et al. 1981), chicken (BANNER et al. 1975), bacteria (NOBLE et al. 1993), trypanosome (WIERENGA et al. 1991), and human (LU et al. 1984; MANDE et al. 1994; MAQUAT et al. 1985) with a high degree of structural similarity shared between the various reported structures. TPI is considered a near perfect enzyme due to its catalytic efficiency; the rate of catalysis is diffusion controlled, suggesting the presence of strong selective pressure throughout the gene's evolution (KNOWLES 1977). TPI is known to exist functionally as a homodimer, and the dimer interaction sites have been well characterized (SCHNEIDER 2000).

In humans, several mutations have been reported that result in TPI deficiency, a progressive disease that eventuates in neuromuscular failure, hemolytic anemia, increased susceptibility to infection, and premature death. At least nine different TPI missense mutations that affect various positions throughout the encoded protein have been identified as the cause of glycolytic enzymopathies (DAAR et al. 1986; DAAR and MAQUAT 1988; CHANG et al. 1993; WATANABE et al. 1996; ARYA et al. 1997; VALENTIN et al. 2000) (supplemental Figure S1 at http://www.genetics.org/supplemental/). Heterozygosity of null human TPI alleles has been observed in 5% of African American and 0.5% of Caucasian populations, although the disease is typically caused by homozygous missense mutations (MOHRENWEISER and FIELEK 1982; MOHRENWEISER 1987). Although prenatal detection is available, there is no treatment for this progressive and devastating neurological disease (ARYA et al. 1996).

TPI has been studied in Drosophila and its mRNA is highly expressed during development and in adult animals (SHAW-LEE et al. 1991). Interestingly, studies of naturally occurring Drosophila populations revealed allozyme polymorphisms, including Tpi^sup S^ (slow) and Tpi^sup F^ (fast) alleles, which indicate the rate of protein anodal electrophoresis migration (VOELKER et al. 1979). Research findings suggest that the Tpi^sup F^ polymorphism (Lys-173-Glu) may alter the "hinged lid" of the enzyme's active site; however, the functional and behavioral consequences of the fast and slow polymorphisms have not yet been characterized (HASSON et al. …

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