Abstract
Myoadenylate deaminase deficiency is the most common metabolic disorder of skeletal
muscle in the Caucasian population, affecting approximately 2% of all individuals.
Although most deficient subjects are asymptomatic, some suffer from exercise-induced
myalgia suggesting a causal relationship between a lack of enzyme activity and muscle
function. In addition, carriers of this derangement in purine nucleotide catabolism
may have an adaptive advantage related to clinical outcome in heart disease. The molecular
basis of myoadenylate deaminase deficiency in Caucasians has been attributed to a
single mutant allele characterized by double C to T transitions at nucleotides +34
and +143 in mRNA encoded by the AMPD1 gene. Polymerase chain reaction-based strategies
have been developed to specifically identify this common mutant allele and are considered
highly sensitive. Consequently, some laboratories preferentially use this technique
over other available diagnostic tests for myoadenylate deaminase deficiency. We previously
identified a G468-T mutation in one symptomatic patient who was only heterozygous
for the common AMPD1 mutant allele. In this report, nine additional individuals with
this compound heterozygous genotype are revealed in a survey of 48 patients with documented
deficiency of skeletal muscle adenosine monophosphate deaminase and exercise-induced
myalgia. Western blot analysis of leftover biopsy material from one of these individuals
does not detect any immunoreactive myoadenylate deaminase polypeptide. Baculoviral
expression of the G468-T mutant allele produces a Q156H substitution enzyme exhibiting
labile catalytic activity. These combined results demonstrate that the G468-T transversion
is dysfunctional and further indicate that AMPD1 alleles harboring this mutation contribute
to the high incidence of partial and complete myoadenylate deaminase deficiency in
the Caucasian population. Consequently, genetic tests for abnormal AMPD1 expression
designed to diagnose patients with metabolic myopathy, and to evaluate genetic markers
for clinical outcome in heart disease should not be based solely on the detection
of a single mutant allele.
Keywords
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References
- Molecular basis of AMP deaminase deficiency in skeletal muscle.Proc Natl Acad Sci USA. 1992; 89: 6457-6461
- deaminase deficiency in 2% of a healthy population.Muscle Nerve. 1995; 18: 234-241
- Clinical heterogeneity and molecular mechanisms in inborn muscle AMP deaminase deficiency.J Inher Metab Dis. 1997; 20: 186-192
- Genetic characteristics of myoadenylate deaminase deficiency.Ann Neurol. 1998; 44: 140-143
- Genetic and other determinants of AMP deaminase activity in healthy adult skeletal muscle.J Appl Physiol. 1998; 85: 1273-1278
- Myoadenylate deaminase deficiency. A common inherited defect with heterogeneous clinical presentation.Neurol Clin. 2000; 18: 185-194
- Myoadenylate deaminase deficiency.in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The metabolic and molecular bases of inherited disease. McGraw-Hill, New York2001: 2627-2638
- Myoadenylate deaminase deficiency: inherited and acquired forms.Biochem Med. 1985; 33: 158-169
- Myoadenylate deaminase deficiency: successful symptomatic therapy by high dose oral administration of ribose.Klin Wochenschr. 1986; 64: 1281-1290
- Beneficial effect of a treatment with xylitol in a patient with myoadenylate deaminase deficiency.Clin Neuropharmacol. 1994; 5: 492-493
- Primary, secondary, and coincidental types of myoadenylate deaminase deficiency.Ann Neurol. 1999; 45: 547-548
- Myoadenylate deaminase deficiency.Muscle Nerve. 1979; 2: 213-216
- Myoadenylate deaminase deficiency or not? Observations on two brothers with exercise-induced pain.J Neurol Sci. 1982; 53: 125-136
- Myoadenylate deaminase deficiency: a clinical and biochemical study in nine families.Muscle Nerve. 1988; 11: 312-317
- Myoadenylate deaminase deficiency does not affect muscle anaplerosis during exhaustive exercise in humans.J Physiol. 2001; 533: 881-889
- Double trouble: combined myophosphorylase and AMP deaminase deficiency in a child homozygous for nonsense mutations at both loci.Neuromusc Disord. 1995; 5: 263-266
- Association of genetically proven deficiencies of myophosphorylase and AMP deaminase: a second case of double trouble.Neuromusc Disord. 1997; 7: 387-389
- Combined defects of muscle phosphofructokinase and AMP deaminase in a child with myoglobinuria.Neurology. 1998; 50: 296-298
- Synergistic heterozygosity: disease resulting from multiple partial defects in one or more metabolic pathways.Mol Genet Metab. 2000; 71: 10-18
- Common variant in AMPD1 gene predicts improved clinical outcome in patients with heart failure.Circulation. 1999; 99: 1422-1425
- A common variant of the AMPD1 gene predicts improved cardiovascular survival in patients with coronary artery disease.J Am Coll Cardiol. 2000; 36: 1248-1252
- Tension myalgia versus myoadenylate deaminase deficiency: a case report.Arch Phys Med Rehabil. 1997; 78: 95-97
- The genetic basis of myoadenylate deaminase deficiency is heterogeneous.Adv Exp Med Biol. 1998; 431: 129-133
- Additional mutations involved in the genesis of myo-adenylate deaminase deficiency (mADD).FASEB J. 1999; 13: A1375
- New method for detection of C34-T mutation in the AMPD1 gene causing myoadenylate deaminase deficiency.Ann Rheum Dis. 1994; 53: 353-354
- A competitive allele-specific oligomers polymerase chain reaction assay for the cis double mutation in AMPD1 that is the major cause of myo-adenylate deaminase deficiency.Mol Diagn. 1997; 2: 121-128
- First missense mutations (R388W and R425H) of AMPD1 accompanied with myopathy found in a Japanese patient.Hum Mutat. 2000; 16: 467-472
- Novel aspects of tetramer assembly and N-terminal domain structure and function are revealed by recombinant expression of human AMP deaminase isoforms.J Biol Chem. 1998; 273: 35118-35125
- Localization of N-terminal sequences in human AMP deaminase isoforms that influence contractile protein binding.Biochem Biophys Res Commun. 2001; 285: 489-495
- Regulation of skeletal muscle ATP catabolism by AMPD1 genotype during sprint exercise in asymptomatic subjects.J Appl Physiol. 2001; 91: 258-264
Article info
Publication history
Accepted:
February 4,
2002
Received in revised form:
January 18,
2002
Received:
October 25,
2001
Identification
Copyright
© 2002 Elsevier Science B.V. Published by Elsevier Inc. All rights reserved.
