Molecular basis of AMP deaminase deficiency in skeletal muscle.

Morisaki, Takayuki; Gross, Manfred; Morisaki, Hiroko; Pongratz, D.; Zöllner, N.; Holmes, Edward W.

doi:10.1073/pnas.89.14.6457

Cited by 202 publications

(161 citation statements)

References 33 publications

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“…Although the precise mechanism of action of MTX in rheumatoid arthritis (RA) is unclear, we agree with Dr. Riksen that the effects are probably contributed by endogenous adenosine release and the interactions of MTX with enzymes involved in the folate pathway (1,2).…”

Section: Replysupporting

confidence: 67%

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Effect of the 34C>T variant in the AMPD1 gene on the clinical response to methotrexate in patients with rheumatoid arthritis: Comment on the article by Wessels et al

Riksen¹,

Rongen²,

Smits³

et al. 2007

Arthritis & Rheumatism

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Effect of the 34C>T variant in the AMPD1 gene on the clinical response to methotrexate in patients with rheumatoid arthritis: comment on the article by Wessels et al To the Editor:We read with interest the pharmacogenetics study by Wessels et al, in which they explored the effect of polymorphisms in genes involved in the metabolism of adenosine on the clinical response to methotrexate (MTX) in patients with rheumatoid arthritis (1). Patients carrying at least 1 allele with the 34CϾT variant in AMPD1 were more likely to have a good clinical response. This finding is relevant, because it offers the possibility to tailor antiinflammatory therapy in individual patients. Unfortunately, the authors do not speculate about the possible underlying mechanism of action.AMPD1 encodes the muscle isoform of adenosine monophospate deaminase (AMPD), which catalyzes the intracellular conversion of AMP to IMP. The 34CϾT variant encodes a truncated protein with loss of function (2). As a consequence, AMP is preferentially converted into adenosine. Endogenous adenosine has potent antiinflammatory properties. Evidence is accumulating that the antiinflammatory effects of MTX are mediated by increased adenosine receptor stimulation (3). Polyglutamated MTX inhibits the enzyme 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, which will increase the intracellular AICAR concentration. Subsequently, AICAR itself inhibits AMPD and adenosine deaminase, which will increase the AMP and adenosine concentrations (3). As such, it is expected that in patients with the 34CϾT variant, the antiinflammatory potential of MTX is reduced rather than increased, because the deficient AMPD enzyme prevents further inhibition by MTX.Moreover, we would like to comment on the use of the European League Against Rheumatism (EULAR) response criteria in the study by Wessels et al, because this may have contributed to a suboptimal interpretation of the data. The authors' primary cutoff point is a Disease Activity Score (DAS) of Յ2.4 at 6 months: they considered patients with a DAS of Յ2.4 to be responders and the rest to be nonresponders. One of the secondary end points is good or moderate improvement, which they define as a decrease of Ͼ1.2 or Ͼ0.6, respectively, in the DAS. The EULAR response criteria, however, define good response as an end DAS of Յ2.4 and a decrease in the DAS of Ͼ1.2. A bad response is defined as a decrease in the DAS of Յ0.6 regardless of the end DAS or a decrease in the DAS of Ͼ0.6 to Յ1.2 if the end DAS remains Ͼ3.7 (4). The use of the EULAR criteria as postulated in the Wessels study leads to pooling of good responders, moderate responders, and nonresponders in the so-called responder group and of moderate responders and nonresponders in the so-called nonresponder group. This can lead to serious confounding.In conclusion, the association between the 34CϾT variant of AMPD1 and the increased likelihood of a good response to MTX cannot be explained with the current paradigm of the mechanism of action of MTX and may be conf...

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Section: Replysupporting

confidence: 67%

“…The 34CϾT variant encodes a truncated protein with loss of function (2). As a consequence, AMP is preferentially converted into adenosine.…”

Section: To the Editormentioning

confidence: 99%

Effect of the 34C>T variant in the AMPD1 gene on the clinical response to methotrexate in patients with rheumatoid arthritis: Comment on the article by Wessels et al

Riksen¹,

Rongen²,

Smits³

et al. 2007

Arthritis & Rheumatism

View full text Add to dashboard Cite

show abstract

“…Yet, the precise interaction between MTX and enzymes in our model is unclear, even though MTX or its polyglutamated form directly inhibits ATIC and AMPD1 and may act through the release of endogenous antiinflammatory adenosine (32). In addition, SNPs in AMPD1, ATIC, and ITPA have been proven to alter their enzyme functionality and may influence the cellular pyrimidine and purine analog balance (35,36,42,48). More importantly, our data showed no significant differences in disease activity measures at baseline or in MTX dosage at 6 months between patients with and those without favorable genotypes (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…Seventeen SNPs in 13 candidate genes related to the MTX mechanism of action, purine and pyrimidine synthesis (30)(31)(32), were selected, taking into consideration the following criteria (33,34): validated SNP, SNP causes nonsynonymous amino acid change, indications for clinical relevance from previous publications, and a preferred minimal genotype frequency of ϳ10% (20,21,(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48).…”

Section: Methodsmentioning

confidence: 99%

A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent‐onset rheumatoid arthritis

Wessels

Kooij

Cessie

et al. 2007

Arthritis & Rheumatism

222

152

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Objective. To develop a clinical pharmacogenetic model to predict the efficacy of methotrexate (MTX) in rheumatoid arthritis (RA).Methods. Two hundred five patients with newly diagnosed RA and active disease were treated with MTX (initiated at a dosage of 7.5 mg/week and increased to 15 mg/week after 4 weeks) and folic acid (1 mg/day). If the Disease Activity Score (DAS) was >2.4 at 3 months, the dosage of MTX was increased up to 25 mg/week. Twenty-four baseline variables possibly influencing disease state and drug response were selected. In addition, 17 polymorphisms in 13 genes related to the MTX mechanism of action, purine and pyrimidine synthesis, were determined. Factors were compared between responders (defined as patients with a DAS <2.4 at 6 months) and nonresponders. In case of differences, a stepwise selection procedure identified the predictors for response. A clinical score was designed by simplifying regression coefficients of the independent variables. Cutoff levels were chosen based on the clinical score, and positive and negative response rates were calculated. An evaluation of the model was performed in a second group of patients.Results. The model for MTX efficacy consisted of sex, rheumatoid factor and smoking status, the DAS, and 4 polymorphisms in the AMPD1, ATIC, ITPA, and MTHFD1 genes. This prediction model was transformed into a scoring system ranging from 0 to 11.5. Scores of <3.5 had a true positive response rate of 95%. Scores of >6 had a true negative response rate of 86%. Sixty percent of the patients were categorized as either responders or nonresponders, whereas 32% of the patients were categorized using a nongenetic model. Evaluation of the model in 38 additional patients with RA supported the results.Conclusion. This study established a model for predicting the efficacy of MTX in patients with RA. This pharmacogenetic model may lead to better-tailored initial treatment decisions in patients with RA.

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“…For example, the gene most dysregulated in mutant TA muscle, adenosine monophosphate deaminase 1 (under-expressed 13.4-fold), catalyzes the deamination of adenosine monophosphate to inosine monophosphate in skeletal muscle, an important step in the purine nucleotide cycle. Mutations in this isozyme are probably the most common cause of metabolic myopathy in humans (5), suggesting that disordered purine metabolism from decreased adenosine monophosphate deaminase 1 expression could potentially play a role in the development of myopathy in H6PD mutant mice.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Hexose-6-phosphate Dehydrogenase Activates the Unfolded Protein Response Pathway and Induces Skeletal Myopathy

Lavery

Walker

Turan

et al. 2008

Journal of Biological Chemistry

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Hexose-6-phosphate dehydrogenase (H6PD) is the initial component of a pentose phosphate pathway inside the endoplasmic reticulum (ER) that generates NADPH for ER enzymes. In liver H6PD is required for the 11-oxoreductase activity of 11␤-hydroxysteroid dehydrogenase type 1, which converts inactive 11-oxo-glucocorticoids to their active 11-hydroxyl counterparts; consequently, H6PD null mice are relatively insensitive to glucocorticoids, exhibiting fasting hypoglycemia, increased insulin sensitivity despite elevated circulating levels of corticosterone, and increased basal and insulin-stimulated glucose uptake in muscles normally enriched in type II (fast) fibers, which have increased glycogen content. Here, we show that H6PD null mice develop a severe skeletal myopathy characterized by switching of type II to type I (slow) fibers. Running wheel activity and electrically stimulated force generation in isolated skeletal muscle are both markedly reduced. Affected muscles have normal sarcomeric structure at the electron microscopy level but contain large intrafibrillar membranous vacuoles and abnormal triads indicative of defects in structure and function of the sarcoplasmic reticulum (SR). SR proteins involved in calcium metabolism, including the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), calreticulin, and calsequestrin, show dysregulated expression. Microarray analysis and real-time PCR demonstrate overexpression of genes encoding proteins in the unfolded protein response pathway. We propose that the absence of H6PD induces a progressive myopathy by altering the SR redox state, thereby impairing protein folding and activating the unfolded protein response pathway. These studies thus define a novel metabolic pathway that links ER stress to skeletal muscle integrity and function. H6PD3 is a bifunctional enzyme that catalyzes the first two steps of the pentose phosphate pathway (1). It is distinct from its cytosolic homolog, glucose-6-phosphate dehydrogenase, in being localized exclusively to the lumen of the endoplasmic reticulum (ER). H6PD converts glucose 6-phosphate to 6-phosphogluconolactonate with the concomitant production of NADPH, thereby maintaining adequate levels of reductive cofactors in the oxidizing environment of the ER (2, 3).One critical role for H6PD is providing NADPH to 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD1), a bi-directional enzyme highly expressed in liver and adipose tissue. 11␤-HSD1 catalyzes both dehydrogenation and oxo-reduction of glucocorticoids, but in vivo it acts predominantly as a NADPHdependent oxoreductase that converts hormonally inactive cortisone to active cortisol (in rodents, 11-dehydrocorticosterone to corticosterone) (4). To investigate the functional interactions of H6PD and 11␤-HSD1 in vivo, we produced mice with a targeted inactivation of H6PD and showed that 11␤-HSD1 predominantly acts as a dehydrogenase in these mice (6). The resulting cellular resistance to corticosterone leads to activation of the hypothalamic-pituitary-adrenal axis and elevat...

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Molecular basis of AMP deaminase deficiency in skeletal muscle.

Cited by 202 publications

References 33 publications

Effect of the 34C>T variant in the AMPD1 gene on the clinical response to methotrexate in patients with rheumatoid arthritis: Comment on the article by Wessels et al

Effect of the 34C>T variant in the AMPD1 gene on the clinical response to methotrexate in patients with rheumatoid arthritis: Comment on the article by Wessels et al

A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent‐onset rheumatoid arthritis

Deletion of Hexose-6-phosphate Dehydrogenase Activates the Unfolded Protein Response Pathway and Induces Skeletal Myopathy

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