• AMPD, AMP deaminase/myoadenylate deaminase
• SNP, single nucleotide polymorphism
• MF PCR-SSCP, multiple fluorescence based PCR single strand conformational polymorphism analysis
• DHPLC, denaturing high performance liquid chromatography analysis

Myoadenylate 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 (10−14%) 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 dysfunction⁴ 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.

In the present study, we attempted to determine other AMPD1 mutations and their distribution in ethnically diverse population groups, in order to better understand AMPD1 deficiency and its functional relevance. We identified 35 variations in and around the AMPD1 locus, including newly identified missense mutations. By estimating SNP haplotypes and defining typical haplotypes of the AMPD1 locus, we were also able to describe a phylogenic tree for ancestral AMPD1 haplotypes …