Recent progress in the molecular genetic analysis of erythroenzymopathy

Fujii, H.; Shiro, Motoo

doi:10.1002/ajh.2830340412

Cited by 32 publications

(7 citation statements)

References 90 publications

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“…The clinical symptoms of the patients are highly variable, ranging from severe haemolytic anaemia requiring transfusions to a fully compensated haemolytic anaemia. Of the two PK genes present in humans, only the PKLR gene coding for the L and R isoenzymes is normally expressed in erythrocytes and mutations therein are thus responsible for the deficiency in red blood cells (Fujii & Miwa, 1990). We present the analysis of DNA and RNA from a patient with severe PK deficiency.…”

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Identification of a novel promoter mutation in the human pyruvate kinase (PK) LR gene of a patient with severe haemolytic anaemia

et al. 1999

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Summary. Using direct sequencing we analysed the pyruvate kinase (PK) LR gene of a patient with severe haemolytic anaemia due to PK deficiency. A novel promoter mutation ¹249delA relative to the translation initiation site and the common 1529A mutation in exon 11 of the gene could be identified. Reverse transcription (RT)-PCR analysis combined with restriction digestion revealed that the ¹249delA mutation leads to a reduction in the amount of mRNA produced from this allele to about 6% of normal. We assume that both mutations would account for the PK deficiency in the compound heterozygous patient.

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Identification of a novel promoter mutation in the human pyruvate kinase (PK) LR gene of a patient with severe haemolytic anaemia

et al. 1999

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“…In addition, neurological impairment has been associated with this disease. GPI deficiency was first described by Baugham et al (11) in 1967, and by 1990 over 40 unrelated affected families have been characterized by assay of enzyme activity (12). Approximately half of the affected individuals are thought to be homozygotes, while the other half appear to be compound heterozygotes (13) .…”

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The characterization of gene mutations for human glucose phosphate isomerase deficiency associated with chronic hemolytic anemia.

Xu¹,

Beutler²

1994

J. Clin. Invest.

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“…The validity of our model is checked by comparing the theoretical predictions with experimental metabolic data for various enzyme deficiencies. For the human erythrocytes, deficiencies of about 20 enzymes, associated with widely different degrees of severity and complexity, have been identified so far (Valentine et al, 1983;Fujii and Miwa, 1990).…”

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“…If, alternatively, changes in the kinetic properties of an enzyme result in a reduced viability of the affected species, the kinetically modified enzyme is usually termed 'deficient'. More and more diseases with unknown origin have been elucidated as being caused by inherited or aquired enzyme deficiencies (Belfiore, 1980) and a deeper understanding of the underlying molecular and cellular alterations represent a rapidly growing field of medical and biochemical research (Fujii and Miwa, 1990). …”

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Use of Mathematical Models for Predicting the Metabolic Effect of Large‐Scale Enzyme Activity Alterations

Schuster

Holzhütter

1995

European Journal of Biochemistry

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There are numerous examples showing that the metabolism of cells can be severely impaired if the activity of only one of the participating enzymes undergoes large-scale alterations, resulting, for example, from spontaneous mutations (inherited or aquired enzymopathies), the administration of toxic drugs or self-inactivation of enzymes during cell aging. However, a quantitative relationship between the degree of enzyme deficiency and the extent of metabolic dysfunction is very difficult to establish by experimental means. An alternative is to tackle this problem by mathematical modelling. Our approach is based on a comprehensive mathematical model of the energy and redox metabolism for human erythrocytes. We calculate stationary states of the cell metabolism, varying the activity of each of the participating enzymes by several orders of magnitude. The metabolic states are then evaluated in terms of a performance function which relates the metabolic variables to the overall functional fitness of the cell. The performance function for the erythrocyte takes into account the homeostasis of three essential metabolic variables : the energetic state (ATP), the reductive capacity (reduced glutathione), and the osmotic state. Based on the behaviour of the performance function at varying enzyme activities, we estimate those ranges of enzyme activities, in which the metabolic alterations should be either tolerable, associated with non-chronic or chronic diseases, or letal. For most enzymopathies, the experimental and clinical observations can be satisfactorily rationalized by the computational results. Moreover, a surprisingly high correlation is found between the range of the activity range where disease is predicted by the model and the observed number of diseased probands.Another objective of our study was to contribute to the theory of metabolic control. The well-elaborated concept of the metabolic control theory is restricted to (infinitely) small activity alterations. In order to quantify the metabolic effect of finite (large-scale) changes in the activity of an enzyme, we propose, as a control measure, the effective activity Em, defined as the relative activity of an enzyme (with respect to the activity in a reference state) required to bring about a change in the stationary value of a metabolic variable by the (finite) factor a. We demonstrate that none of the existing extrapolation methods using the conventional control coefficient is capable to provide reliable predictions of the effective activities for all enzymes of erythrocyte metabolism.

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Recent progress in the molecular genetic analysis of erythroenzymopathy

Cited by 32 publications

References 90 publications

Identification of a novel promoter mutation in the human pyruvate kinase (PK) LR gene of a patient with severe haemolytic anaemia

Identification of a novel promoter mutation in the human pyruvate kinase (PK) LR gene of a patient with severe haemolytic anaemia

The characterization of gene mutations for human glucose phosphate isomerase deficiency associated with chronic hemolytic anemia.

Use of Mathematical Models for Predicting the Metabolic Effect of Large‐Scale Enzyme Activity Alterations

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