Haplotype analysis of human AMPD1 gene: origin of common mutant allele

yoadenylate deaminase is a skeletal muscle specific isoenzyme of AMP deaminase (AMPD; EC 3.5.4.6) that plays an important role in regulating adenylate energy charge and nucleotide metabolism. An inherited defect of this enzyme has been reported to be due to a single mutant allele with two linked mutations of C34T (exon 2, Q12X) and C143T (exon 3, P48L) of the AMPD1 gene in almost all cases. 1 2 Further, a previous report showed a very high frequency (10214%) of the C34T allele in whites and African Americans, 2 although it has not been found in a Japanese population. Although most individuals with homozygous C34T alleles are assumed to be asymptomatic, some have been reported to show a relatively mild clinical phenotype including exercise induced myalgia. 1 Recently, additional findings for missense mutations were reported in Japanese (R388W and R425H) 3 and in whites (G468T) 4 who showed muscle weakness and myalgia. Therefore, the relationship between abnormal purine nucleotide catabolism and skeletal muscle dysfunction 4 is intriguing. In addition, other studies have reported that the C34T allele correlates with improved clinical outcome in patients with heart disease. 5 6 We speculated that reduced AMPD activity in skeletal muscle would increase the production of the cardioprotection molecule, adenosine, resulting in increased levels of adenosine in the circulating system, although the fundamental mechanisms responsible for the disorder due to AMPD mutations are unclear.