Myoadenylate Deaminase Deficiency: A New Disease of Muscle

Fishbein, William N.; Armbrustmacher, Vernon W.; Griffin, Jasper

doi:10.1126/science.644316

Cited by 262 publications

(114 citation statements)

References 19 publications

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“…Under such conditions, AMPD, by draining AMP to IMP, plays a critical role in the stabilization of adenylate energy charge. Consequently, defects in AMPD lead to exercise-induced muscle symptoms such as early fatigue and is the most common muscle enzyme defect in humans (Fishbein et al 1978). While there are three AMPD human isoforms, in Saccharomyces cerevisiae, a mutation at a single locus (named AMD1; Figure 1) abolishes AMPD activity (Meyer et al 1989).…”

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confidence: 99%

Phenotypic Consequences of Purine Nucleotide Imbalance inSaccharomyces cerevisiae

et al. 2009

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Coordinating homeostasis of multiple metabolites is a major task for living organisms, and complex interconversion pathways contribute to achieving the proper balance of metabolites. AMP deaminase (AMPD) is such an interconversion enzyme that allows IMP synthesis from AMP. In this article, we show that, under specific conditions, lack of AMPD activity impairs growth. Under these conditions, we found that the intracellular guanylic nucleotide pool was severely affected. In vivo studies of two AMPD homologs, Yjl070p and Ybr284p, indicate that these proteins have no detectable AMP, adenosine, or adenine deaminase activity; we show that overexpression of YJL070c instead mimics a loss of AMPD function. Expression of the yeast transcriptome was monitored in a AMPD-deficient mutant in a strain overexpressing YJL070c and in cells treated with the immunosuppressive drug mycophenolic acid, three conditions that lead to severe depletion of the guanylic nucleotide pool. These three conditions resulted in the up-or downregulation of multiple transcripts, 244 of which are common to at least two conditions and 71 to all three conditions. These transcriptome results, combined with specific mutant analysis, point to threonine metabolism as exquisitely sensitive to the purine nucleotide balance.T HE purine nucleotides, ATP and GTP, are involved in almost all aspects of cellular life. In addition to their role as building blocks of nucleic acids, adenylic and guanylic nucleotides have specific roles. For example, GTP is critical for translation and for signaling through GTPases, while ATP is the major energyproviding molecule in the cell. In yeast, intracellular concentrations of ATP and GTP are clearly different ($5 and 1.5 mm, respectively; Breton et al. 2008;Gauthier et al. 2008), most probably as the result of regulatory processes that maintain homeostasis. In most eukaryotic cells, including yeast, adenylic and guanylic nucleotides either are synthesized from a common precursor (IMP) or are recycled from preformed bases or nucleosides (Figure 1). While most enzymes involved in these processes have been identified, the physiological consequences of purine nucleotide imbalance are far from being understood. Interestingly, drugs specifically inhibiting GTP synthesis, such as mycophenolic acid (MPA), have a strong immunosuppressive effect and are now widely used to limit allograft rejection. We have previously established the effect of MPA on the yeast proteome and have identified numerous yeast mutants hypersensitive to this drug (Desmoucelles et al. 2002). MPA effects are due to GTP shortage, since they are reversed by exogenous guanine, allowing replenishment of the GTP pool. However, drugs often have secondary effects and can be detoxified and/or diluted during cell growth. As an alternative, consequences of purine nucleotide imbalance can be investigated using yeast mutants. In two previous studies, we have used specific mutants to increase the GTP pool or decrease the ATP pool (Breton et al. 2008;Gauthier et al. 20...

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confidence: 99%

Phenotypic Consequences of Purine Nucleotide Imbalance inSaccharomyces cerevisiae

et al. 2009

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“…A normal response to the exercise is a several-fold increase in both lactate and ammonia concentrations (5,6). In MADA-deficient subjects, lactate concentrations increase, but little or no change is observed in ammonia levels (2,(5)(6)(7)(8). Such a response has been reported in all MADA-deficient subjects described to date, but there have been many falsepositive results in normal subjects (7,9).…”

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confidence: 84%

“…A deficiency of MADA activity, perhaps the most common cause of metabolic myopathy , has been reported in association with skeletal muscle dysfunction (2). Although the clinical picture is variable, most MADA-deficient subjects experience easy fatigue, cramps, and postexertional myalgias (2)(3)(4).…”

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Myoadenylate deaminase deficiency and forearm ischemic exercise testing

Valen

Nakayama

Veum

et al. 1987

Arthritis & Rheumatism

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Myoadenylate deaminase (MADA) deficiency has been associated with symptoms of postexertional aches, cramps, weakness, and skeletal muscle dysfunction. Measurement of plasma lactate and ammonia concentrations after forearm ischemic exercise has been suggested as a screening test for this disorder. We performed forearm ischemic tests on 3 patients with histochemically defined MADA deficiency and 13 healthy control subjects, in a standardized fashion. Our results demonstrated that subject effort and/or performance during the exercise portion of testing is a critical variable. In addition to lactate and ammonia, plasma purine compounds (adenosine, inosine, and hypoxanthine) were measured. The finding of decreased purine release after exercise in MADA-deficient patients compared with that in normal individuals increases the specificity of the test and supports the hypothesis that disordered purine metabolism occurs in MADA deficiency.Myoadenylate deaminase (MADA) (EC 3.5.4.6) catalyzes the deamination of AMP to IMP in skeletal muscle and plays an important role in the purine

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“…Fishbein et a1 (4) developed a sensitive histochemical stain for the detection of MADA in frozen skeletal muscle samples, and in 1978, they described 5 patients with MADA deficiency who presented with postexertional muscle weakness and cramps (5). More than 40 cases of MADA deficiency have now been described, and the major functional and metabolic abnormalities associated with this disorder have been summarized (6).…”

Section: Brief Report Progressive Myalgias and Polyarthralgias In A Pmentioning

confidence: 99%

Progressive myalgias and polyarthralgias in a patient with myoadenylate deaminase deficiency

Lally

Friedman

Kaplan

1985

Arthritis & Rheumatism

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Myoadenylate Deaminase Deficiency: A New Disease of Muscle

Cited by 262 publications

References 19 publications

Phenotypic Consequences of Purine Nucleotide Imbalance inSaccharomyces cerevisiae

Phenotypic Consequences of Purine Nucleotide Imbalance inSaccharomyces cerevisiae

Myoadenylate deaminase deficiency and forearm ischemic exercise testing

Progressive myalgias and polyarthralgias in a patient with myoadenylate deaminase deficiency

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